抗菌

Copyright©1999,AmericanSocietyforMicrobiology.AllRightsReserved.

Vol.12,No.4

PlantProductsasAntimicrobialAgents

MARJORIEMURPHYCOWAN*

DepartmentofMicrobiology,MiamiUniversity,Oxford,Ohio45056

INTRODUCTION.......................................................................................................................................................564BriefHistory............................................................................................................................................................565MAJORGROUPSOFANTIMICROBIALCOMPOUNDSFROMPLANTS...................................................565PhenolicsandPolyphenols....................................................................................................................................565Simplephenolsandphenolicacids..................................................................................................................565Quinones..............................................................................................................................................................568Flavones,flavonoids,andflavonols..................................................................................................................568Tannins.................................................................................................................................................................569Coumarins............................................................................................................................................................571TerpenoidsandEssentialOils..............................................................................................................................571Alkaloids...................................................................................................................................................................572LectinsandPolypeptides.......................................................................................................................................572Mixtures...................................................................................................................................................................572OtherCompounds...................................................................................................................................................573EXPERIMENTALAPPROACHES...........................................................................................................................573ExtractionMethods................................................................................................................................................573Efficacy......................................................................................................................................................................574Invitroexperiments...........................................................................................................................................574(i)Bacteriaandfungi.....................................................................................................................................574(ii)Viruses.......................................................................................................................................................574(iii)Protozoaandhelminths.........................................................................................................................575Invivotestingofphytochemicals.....................................................................................................................575Clinicaltrialsinhumans...................................................................................................................................575PLANTSWITHEFFICACYAGAINSTHUMANIMMUNODEFICIENCYVIRUS.........................................577COMMERCIALAVAILABILITYANDSAFETYOFCOMPOUNDS.................................................................577CONCLUSIONSANDFUTUREDIRECTIONS....................................................................................................577ACKNOWLEDGMENTS...........................................................................................................................................577REFERENCES............................................................................................................................................................577

INTRODUCTION

“EatleeksinMarchandwildgarlicinMay,andalltheyearafterthephysiciansmayplay.”

TraditionalWelshrhyme(230)“Anappleadaykeepsthedoctoraway.”

TraditionalAmericanrhymeFindinghealingpowersinplantsisanancientidea.Peopleonallcontinentshavelongappliedpoulticesandimbibedinfusionsofhundreds,ifnotthousands,ofindigenousplants,datingbacktoprehistory.ThereisevidencethatNeanderthalsliving60,000yearsagoinpresent-dayIraqusedplantssuchashollyhock(211,224);theseplantsarestillwidelyusedineth-nomedicinearoundtheworld.Historically,therapeuticresultshavebeenmixed;quiteoftencuresorsymptomreliefresulted.Poisoningsoccurredatahighrate,also.Currently,oftheone-quartertoone-halfofallpharmaceuticalsdispensedintheUnitedStateshavinghigher-plantorigins,veryfewarein-tendedforuseasantimicrobials,sincewehavereliedonbac-terialandfungalsourcesfortheseactivities.Sincetheadventofantibioticsinthe1950s,theuseofplantderivativesasantimicrobialshasbeenvirtuallynonexistent.

*Mailingaddress:DepartmentofMicrobiology,MiamiUniversity,MiddletownCampus,4200EastUniversityBlvd.,Middletown,OH45042.Phone:(513)727-3231.Fax:(513)727-3367.E-mail:cowanmm@muohio.edu.

564

Clinicalmicrobiologistshavetworeasonstobeinterestedinthetopicofantimicrobialplantextracts.First,itisverylikelythatthesephytochemicalswillfindtheirwayintothearsenalofantimicrobialdrugsprescribedbyphysicians;severalareal-readybeingtestedinhumans(seebelow).Itisreportedthat,onaverage,twoorthreeantibioticsderivedfrommicroorgan-ismsarelaunchedeachyear(43).Afteradownturninthatpaceinrecentdecades,thepaceisagainquickeningasscien-tistsrealizethattheeffectivelifespanofanyantibioticislimited.Worldwidespendingonfindingnewanti-infectiveagents(includingvaccines)isexpectedtoincrease60%fromthespendinglevelsin1993(7).Newsources,especiallyplantsources,arealsobeinginvestigated.Second,thepublicisbe-comingincreasinglyawareofproblemswiththeoverprescrip-tionandmisuseoftraditionalantibiotics.Inaddition,manypeopleareinterestedinhavingmoreautonomyovertheirmedicalcare.Amultitudeofplantcompounds(oftenofunre-liablepurity)isreadilyavailableover-the-counterfromherbalsuppliersandnatural-foodstores,andself-medicationwiththesesubstancesiscommonplace.Theuseofplantextracts,aswellasotheralternativeformsofmedicaltreatments,isenjoy-inggreatpopularityinthelate1990s.Earlierinthisdecade,approximatelyone-thirdofpeoplesurveyedintheUnitedStatesusedatleastone“unconventional”therapyduringthepreviousyear(60).Itwasreportedthatin1996,salesofbo-tanicalmedicinesincreased37%over1995(116).Itisspecu-latedthattheAmericanpublicmaybereactingtooverpre-

VOL.12,1999scriptiontheing,19thofpurging,centurysometimestoxicdrugs,justastheirpredecessorsofand(seecalomelbelow)(248).

reactedtotheoveruseofbleed-BriefHistory

plantsItisestimatedthatofonEarth(25).Athererelativelyare250,000smallpercentageto500,000(1speciesto10%)ofspecies.thesepurposesItareisusedpossibleasfoodsthatevenbybothmorehumansareandotheranimalmentioned(146).tury300toHippocrates400medicinal(inplantsthelateusedformedicinal(195).fifthcenturyB.C.)plantA.D.,macopoeias.catalogDioscorideswhichbecamewrotetheDeMateriaMedicaIn,theamedicinalfirstcen-healingjoyedplants.TheIndeed,Bibleoffersfrankincensedescriptionsprototypeformodernphar-andofmyrrhapproximatelyprobably30erties.theiremployedReportedstatustoofhavegreatantisepticworthdueproperties,totheirmedicinalen-theyprop-forestalledasmouthwashes.ThefallofancientwereevennalWesternadvancesintheunderstandingcivilizationsofmedici-ceuticalsplants,thebeingwithdestroyedmuchoftheorlostdocumentation(211).DuringoftheplantDarkpharma-Ages,andArabbusytobuildworlduponcontinuedthem.Oftocourse,excavateAsiantheirculturesownolderworksRenaissancecompilingbuiltyearstheirsawownarevivalpharmacopoeia.ofancientmedicine,IntheWest,werealsothestrands—theirNorthlargelywhichwasAmerica’sonplantmedicinals.

datingusebyhistoryofplantmedicinalusefollowstwoamongfromcentury.AmericansprehistoryindigenousofEuropean(243),andcultures(NativeAmericans),origin,an“alternative”beginninginmovementreviewedNativeHeextensivelyAmericaninaseriesuseofofarticlesplantmedicinalsthe19thbyhasbeenbyusevariousreportedNativethatwhileAmerican1,625groupsspeciesasofplantsMoermanhavebeen(146).usedapproximatelyasdrugs(116).neither18,000Accordingfood,2,564havefoundspeciesoftoplantshiscalculations,thisleavesselectedfoodornumbernorofdrugs.plantSpeculationsaswhichtohowwereandusedwhyforabotanicalsAmongdrugsisEuropeansfascinatingbutspecieslivingoutsidecameinthetheintoNewscopeuseWorld,offorthiseitherthereview.fooduseofmedicinalwasareactionagainstinvasiveortoxicmainstreamWendellcouldHolmespracticesnotedofthethatday.medicalNolesstreatmentsaluminaryinthantheOliver1800sofandmercurybedangerousbathsinandLondonineffective.“barberExamplesshops”toincludetreatthesyphilisuseHolmesdangerousbewrote,“Ifhallucinogensthewholemateriaasatuberculosismedicaas“cure.”nowusedIn1861mankind—andsunktothebottomternativealltheofworsethesea,fortheitwouldfishes”be(92).alltheInbettercould1887,foral-theHomeopathicpractitionersPharmacopoeiacompiledoftheirowncatalogs,notablyantimicrobialMainstreamtionalandmedicineotherisdrugsincreasinglythederivedreceptiveUnitedStates.

fromtotheuseofsizedviral,derivatives)antibiotics(productsbecomeineffectiveofmicroorganismsplants,andasnew,ortheirastradi-particularlysynthe-drivingdiseasesinfactorremainfortheintractablerenewedinteresttothisintypeplantofdrug.antimicrobialsAnotherextinctionthepastchemists(131).20yearsTherehasbeenisafeelingtherapidrateof(plant)speciestiallysizedusefulandphytochemicalmicrobiologistsstructuresalikethatamongwhichthemultitudenatural-productscouldbeofsynthe-poten-ismacology),ascientificchemicallydisciplineisatriskknownofbeingaslostethnobotanyirretrievably(or(25).Thereknowledgeassembledwhosegoalbyisindigenoustoutilizethepeoplesimpressiveethnophar-aboutthearrayplant

ofANTIMICROBIALPLANTCHEMICALS565

and182,animaldeficiency203,234).productsLastly,theytheascendancyhaveusedtoofmaintainthehumanhealthimmuno-(77,theinplantvirus(HIV)hasspurredintensiveinvestigationintoernunderdevelopedderivativesnationswhichwithmaylittlebeeffective,accesstoespeciallyexpensiveforWest-usenewmedicines.(ForacomprehensivereviewofthealsThisanti-HIVagents,seereference51.)

searchforuse,inthereviewUniteddescribesStates,therangingcurrentfromstateextractsofplantcommonlyantimicrobi-pectedlargelypoundsandbytestedthebylayresearcherscommunity,andtosubstancesbeingpros-inareica,beingpotentiallythearealsosoughtaddressed.fareffectiveandAnwideintreatingHIVclinicians.infections,Also,whichcom-attemptforprobableisalsomadeuseintoNorthsummarizeAmer-products,currentusesincestatecliniciansofknowledgeinthisofcountryrelativelywillundefinedencounterherbaladdressamongitthepatientsworldwideintheuseUnitedofStates.ThisreviewdoestheirnotAmerica.focusesonplantsandtheirextractsplantsascurrentlymedicinals,inusebut,inrather,NorthpropertiesOnlyphytochemicalsreportedtohaveanti-infectivesystemareexamined.Themanyplantsusedasimmunetheseareboundaries,boostersarereportsoutsidecitedtheinpurviewthepeer-reviewedofthisreview.literatureWithinualofplant-derivedgivenheaviestmedicationsemphasis.Detailedcanbefounddescriptionsinthefirstofindivid-lishedthebyPhysician’sMedicalEconomicsDeskReferenceCompanyforHerbaleditionin1998.

Medicines,pub-MAJORCOMPOUNDSGROUPSOFFROMANTIMICROBIAL

PLANTS

substances,Plantshaveanalmostlimitlessabilitytosynthesizearomatictutedmostofwhicharephenolsortheiroxygen-substi-whichderivatives(76).Mostaresecondarymetabolites,oftosubstancesbelessatleastthan12,00010%ofhavethebeentotalisolated,anumberestimatedtionterpenoids,bymicroorganisms,serveasplant(195).Inmanycases,theseinsects,defensemechanismsagainstpreda-nins)responsibleareresponsiblegiveplantstheirodors;andothersherbivores.(quinonesSome,andsuchtan-aschilihumanspeppers),forplantflavorforplant(e.g.,pigment.theterpenoidManycompoundscapsaicinfromarebletoseasonandfoodsomeyieldoftheusefulsamemedicinalherbsandspicesusedbyeralUseful1).

compounds(Ta-categories,antimicrobialdescribedphytochemicalsbelowandsummarizedcanbedividedinTableintosev-2.

PhenolicsandPolyphenols

bioactiveSimplephenolsandphenolicacids.Someofthesimplestnolicphytochemicalsconsistofasinglesubstitutedphe-tativesring.Cinnamicandcaffeicacidsarecommonrepresen-whichofawidegroupofphenylpropane-derivedcompoundsacid,Theareinthehighestoxidationstate(Fig.1).

andwhichcommoniseffectiveherbstarragonagainstvirusesandthyme(245),bothbacteriacontain(31,caffeicshownCatecholfungi(58).

224),groups,tobeandtoxicpyrogalloltomicroorganisms.botharehydroxylatedphenols,hydroxylandtoincreasedtheirrelativegroupspyrogallolhasthree.TheCatecholsite(s)andhasnumbertwoϪOHoftoxicityonthephenoltomicroorganisms,grouparethoughtwithevidencetoberelatedaddition,phenolssomehydroxylationauthorshaveresultsfoundinincreasedthatmoretoxicityhighly(76).thatInthoughttoarebemoreresponsibleinhibitoryforphenolic(192,231).toxicityThetomechanismsoxidizedmicroorgan-

566COWAN

TABLE1.PlantscontainingantimicrobialactivityaCLIN.MICROBIOL.REV.

CommonnameScientificnameCompoundClassActivitydRelativetoxicitybReference(s)cAlfalfaAllspiceAloeApple

AshwagandhaAvelozBaeltreeBalsampearBarberryBasilBay

BetelpepperBlackpepperBlueberry

BrazilianpeppertreeBuchuBurdockButtercupCaraway

CascarasagradaCashew

Castorbean

CeyloncinnamonChamomile

MedicagosativaPimentadioicaAloebarbadensis,AloeveraMalussylvestris

WithaniasomniferumEuphorbiatirucalliAeglemarmelos

MomordicacharantiaBerberisvulgarisOcimumbasilicumLaurusnobilisPiperbetelPipernigrum

Vacciniumspp.

SchinusterebinthifoliusBarosmasetulinaArctiumlappaRanunculusbulbosusCarumcarvi

RhamnuspurshianaAnacardiumpulsatillaRicinuscommunisCinnamomumverumMatricariachamomilla

?

EugenolLatex

PhloretinWithafarinA?

Essentialoil?

BerberineEssentialoilsEssentialoils

Catechols,eugenolPiperineFructose

TerebinthoneEssentialoilProtoanemoninTanninsSalicylicacids?

Essentialoils,others

Anthemicacid—

Nordihydroguai-areticacidCapsaicinEugenolCocaine???

FructoseOther?

Essentialoil?Tannin—

FabatinAllicin,ajoene

Essentialoil

ComplexmixtureFlavonoidderivativeLactoneTerpenoidAlkaloidTerpenoidsTerpenoidsEssentialoilsAlkaloid

MonosaccharideTerpenoidsTerpenoid

Polyacetylene,tannins,terpenoidsLactoneCoumarinsPolyphenolsAnthraquinonePolyphenolsTerpenoids,tanninsPhenolicacidCoumarinsLignanTerpenoidTerpenoidAlkaloid

Gram-positiveorganismsGeneral

Corynebacterium,Salmonella,Streptococcus,S.aureusGeneral

Bacteria,fungiS.aureusFungiGeneral

Bacteria,protozoaSalmonella,bacteriaBacteria,fungiGeneral

Fungi,Lactobacillus,Micrococcus,E.coli,E.faecalisE.coliGeneralGeneral

Bacteria,fungi,virusesGeneral

Bacteria,fungi,virusesViruses,bacteria,fungiP.acnes

Bacteria,fungiGeneralGeneral

M.tuberculosis,S.typhi-murium,S.aureus,helminthsViruses

SkinbacteriaBacteria

General

Gram-negativeand-positivecocciGeneralGeneral

Bacteria,fungiBacteria

C.albicans,S.cerevisiaeBacteriaGeneralBacteria,virusesBacteriaGeneralGeneral

E.coli,Sporothrixschenckii,Staphylococcus,Tricho-phytonGeneral

Bacteria,Giardiaduodenale,trypanosomesPlasmodiaM.lepraeFungi

2.32.52.73.00.00.01.02.02.50.71.01.0

136101179140,16324178158

1.02.02.32.01.0

24,26,83,193

0.02.02.3

91

26,83,1932442,107

ChapparalChilipeppers,paprikaCloveCoca

CockleColtsfoot

Coriander,cilantroCranberryDandelionDill

EchinaceaEucalyptusFavabeanGambogeGarlicGinsengGlorylilyGoldensealGotukola

Grapefruitpeel

LarreatridentataCapsicumannuumSyzygiumaromaticumErythroxylumcocaAgrostemmagithagoTussilagofarfaraCoriandrumsativumVacciniumspp.TaraxacumofficinaleAnethumgraveolensEchinaceaeangustifolia

EucalyptusglobulusViciafaba

GarciniahanburyiAlliumsativumPanaxnotoginsengGloriosasuperbaHydrastiscanadensisCentellaasiaticaCitrusparadisa

2.02.01.70.51.02.0

MonosaccharideTerpenoidPolyphenolTerpenoidThioninResinSulfoxide

SulfatedterpenoidsSaponinsAlkaloidAlkaloidsTerpenoidTerpenoid

17,158,159

2.73.01.50.52.70.02.01.7

153

150,187,188250

ColchicineBerberine,hydrastineAsiatocoside

73163209

Continuedonfollowingpage

VOL.12,1999

TABLE1—Continued

Commonname

Scientificname

Compound

Class

ANTIMICROBIALPLANTCHEMICALS567

ActivitydRelativetoxicitybReference(s)cGreenteaCamelliasinensisCatechinFlavonoid

Harmel,rueHempHennaHops

HorseradishHyssop

(Japanese)herbLantana—

Lavender-cottonLegume(WestAfrica)LemonbalmLemonverbenaLicorice

Luckynut,yellowMace,nutmegMarigoldMesquite

MountaintobaccoOak

OliveoilOnion

OrangepeelOregongrapePaod’arcoPapaya

Pasque-flowerPeppermintPeriwinklePeyotePoinsettiaPoppyPotato

ProstrateknotweedPurpleprairiecloverQuinine

Rauvolfia,chandraRosemarySainfoinSassafrasSavorySenna

Smoothhydrangea,sevenbarksSnakeplantSt.John’swort

Sweetflag,calamusTansyTarragon

PeganumharmalaCannabissativaLawsoniainermisHumuluslupulusArmoraciarusticanaHyssopusofficinalisRabdosiatrichocarpaLantanacamaraLawsonia

Santolinachamae-cyparissus

MillettiathonningiiMelissaofficinalisAloysiatriphyllaGlycyrrhizaglabraThevetiaperuvianaMyristicafragransCalendulaofficinalisProsopisjulifloraArnicamontanaQuercusrubraOleaeuropaeaAlliumcepaCitrussinensisMahoniaaquifoliaTabebuia

CaricapapayaAnemonepulsatillaMenthapiperitaVincaminor

LophophorawilliamsiiEuphorbiapulcherrimaPapaversomniferumSolanumtuberosumPolygonumavicularePetalostemumCinchonasp.

RauvolfiaserpentinaRosmarinusofficinalisOnobrychisviciifoliaSassafrasalbidumSaturejamontanaCassiaangustifoliaHydrangeaarborescensRiveacorymbosa

HypericumperforatumAcoruscalamusTanacetumvulgareArtemisiadracunculus

?

␤-ResercyclicacidGallicacid

Lupulone,humulone—

—

TrichorabdalA?

Lawsone?

AlpinumisoflavoneTanninsEssentialoilGlabrol????

HelaninsTannins

Quercetin(availablecommercially)HexanalAllicin?

BerberineSesquiterpenesLatex

AnemoninsMentholReserpineMescaline?

Opium??

PetalostemumolQuinineReserpineEssentialoilTannins?

CarvacrolRhein?

?

Hypericin,others?

EssentialoilsCaffeicacids,tannins

OrganicacidPhenolic

Phenolicacids(Hemi)terpenoidsTerpenoidsTerpenoidsTerpeneQuinoneFlavonePolyphenolsTerpenoid?

Phenolicalcohol

GeneralShigellaVibrioS.mutansViruses

Bacteria,fungi

BacteriaandvirusesS.aureusGeneral

GeneralViruses

HelicobacterpyloriGeneral

M.tuberculosis

Gram-positivebacteria,CandidaSchistosoma

VirusesAscaris

E.coli,M.tuberculosis,S.aureus

S.aureus,M.tuberculosisPlasmodiumGeneralBacteriaGeneralGeneral

2.0

1.01.01.52.3

235226166113

1.0—1.0

108213175

1.52.00.01.52.71.52.0

245

LactonesPolyphenolsFlavonoidAldehydeSulfoxideTerpenoidAlkaloid

Terpenoids

Mixofterpenoids,organicacids,alkaloidsLactoneTerpenoidAlkaloidAlkaloid

AlkaloidsandothersFlavonolAlkaloidAlkaloidTerpenoidPolyphenolsTerpenoid

Anthraquinone

113

General

Bacteria,CandidaFungi

Plasmodium

Trypansomes,generalFungiGeneralBacteriaGeneralGeneralGeneralGeneralGeneral

Bacteria,fungiGeneral

Bacteria,fungiPlasmodiumspp.GeneralGeneral

RuminalbacteriaHelminthsGeneralS.aureusGeneral

GeneralGeneral

EntericbacteriaHelminths,bacteriaViruses,helminths

12023920916373

34,168,191

2.01.03.00.51.51.50.00.52.02.02.01.02.32.02.02.02.31.01.70.72.02.5

100

1056

AnthraquinoneTerpenoidTerpenoidPolyphenols

245

Continuedonfollowingpage

568COWAN

TABLE1—Continued

CLIN.MICROBIOL.REV.

CommonnameScientificnameCompoundClassActivitydRelativetoxicitybReference(s)cThymeThymusvulgaris

TreebardPodocarpusnagi

CaffeicacidThymolTannins—

TotarolNagilactone

Terpenoid

PhenolicalcoholPolyphenolsFlavonesFlavonolLactone

Viruses,bacteria,fungi2.5

P.acnes,othergram-positivebacteriaFungiGeneral

0.0

12312112214

2.7

Tua-TuaTurmericValerianWillowWintergreenWoodruffYarrow

Yellowdock

abJatropha

gossyphiifoliaCurcumalongaValerianaofficinalisSalixalbaGaultheriaprocumbensGaliumodoratumAchilleamillefoliumRumexcrispus

?

CurcuminTurmericoilEssentialoilSalicinTanninsEssentialoilTannins—??

TerpenoidsTerpenoid

PhenolicglucosidePolyphenolsTerpenoidPolyphenolsCoumarin

Bacteria,protozoaGeneral

General

GeneralViruses

Viruses,helminthsE.coli,Salmonella,Staphylococcus

1.03.02.31.0

26,83,19324

PlantswithactivityonlyagainstHIVarelistedinTable6.0,verysafe;3,verytoxic.Datafromreference58.cTableisbasedondatacompiledfromreferences58and224;additionalreferencesarelistedhere.d“General”denotesactivityagainstmultipletypesofmicroorganisms(e.g.,bacteria,fungi,andprotozoa),and“bacteria”denotesactivityagainstgram-positiveandgram-negativebacteria.

ismsincludeenzymeinhibitionbytheoxidizedcompounds,possiblythroughreactionwithsulfhydrylgroupsorthroughmorenonspecificinteractionswiththeproteins(137).

PhenoliccompoundspossessingaC3sidechainatalowerlevelofoxidationandcontainingnooxygenareclassifiedasessentialoilsandoftencitedasantimicrobialaswell.Eugenolisawell-characterizedrepresentativefoundincloveoil(Fig.1).Eugenolisconsideredbacteriostaticagainstbothfungi(58)andbacteria(224).

Quinones.Quinonesarearomaticringswithtwoketonesubstitutions(Fig.1).Theyareubiquitousinnatureandarecharacteristicallyhighlyreactive.Thesecompounds,beingcol-ored,areresponsibleforthebrowningreactionincutorin-juredfruitsandvegetablesandareanintermediateinthemelaninsynthesispathwayinhumanskin(194).Theirpres-enceinhennagivesthatmaterialitsdyeingproperties(69).Theswitchbetweendiphenol(orhydroquinone)anddiketone(orquinone)occurseasilythroughoxidationandreductionreactions.Theindividualredoxpotentialoftheparticularqui-none-hydroquinonepairisveryimportantinmanybiologicalsystems;witnesstheroleofubiquinone(coenzymeQ)inmam-malianelectrontransportsystems.VitaminKisacomplexnaphthoquinone.Itsantihemorrhagicactivitymayberelatedtoitseaseofoxidationinbodytissues(85).Hydroxylatedaminoacidsmaybemadeintoquinonesinthepresenceofsuitableenzymes,suchasapolyphenoloxidase(233).There-actionfortheconversionoftyrosinetoquinoneisshowninFig.2.

Inadditiontoprovidingasourceofstablefreeradicals,quinonesareknowntocomplexirreversiblywithnucleophilicaminoacidsinproteins(210),oftenleadingtoinactivationoftheproteinandlossoffunction.Forthatreason,thepotentialrangeofquinoneantimicrobialeffectsisgreat.Probabletar-getsinthemicrobialcellaresurface-exposedadhesins,cellwallpolypeptides,andmembrane-boundenzymes.Quinonesmayalsorendersubstratesunavailabletothemicroorganism.Aswithallplant-derivedantimicrobials,thepossibletoxicef-fectsofquinonesmustbethoroughlyexamined.

Kazmietal.(112)describedananthraquinonefromCassiaitalica,aPakistanitree,whichwasbacteriostaticforBacillusanthracis,Corynebacteriumpseudodiphthericum,andPseudo-monasaeruginosaandbactericidalforPseudomonaspseudoma-lliae.Hypericin,ananthraquinonefromSt.John’swort(Hype-ricumperforatum),hasreceivedmuchattentioninthepopularpresslatelyasanantidepressant,andDukereportedin1985thatithadgeneralantimicrobialproperties(58).

Flavones,flavonoids,andflavonols.Flavonesarephenolicstructurescontainingonecarbonylgroup(asopposedtothetwocarbonylsinquinones)(Fig.1).Theadditionofa3-hy-droxylgroupyieldsaflavonol(69).Flavonoidsarealsohy-droxylatedphenolicsubstancesbutoccurasaC6-C3unitlinkedtoanaromaticring.Sincetheyareknowntobesynthesizedbyplantsinresponsetomicrobialinfection(56),itshouldnotbesurprisingthattheyhavebeenfoundinvitrotobeeffectiveantimicrobialsubstancesagainstawidearrayofmicroorgan-isms.Theiractivityisprobablyduetotheirabilitytocomplexwithextracellularandsolubleproteinsandtocomplexwithbacterialcellwalls,asdescribedaboveforquinones.Morelipophilicflavonoidsmayalsodisruptmicrobialmembranes(229).

Catechins,themostreducedformoftheC3unitinflavonoidcompounds,deservespecialmention.Theseflavonoidshavebeenextensivelyresearchedduetotheiroccurrenceinoolonggreenteas.Itwasnoticedsometimeagothatteasexertedantimicrobialactivity(227)andthattheycontainamixtureofcatechincompounds.ThesecompoundsinhibitedinvitroVibriocholeraeO1(25),Streptococcusmutans(23,185,186,228),Shigella(235),andotherbacteriaandmicroorganisms

VOL.12,1999ANTIMICROBIALPLANTCHEMICALS

TABLE2.Majorclassesofantimicrobialcompoundsfromplants

569

ClassSubclassExample(s)MechanismReference(s)

PhenolicsSimplephenolsPhenolicacidsQuinonesFlavonoidsFlavonesFlavonolsTannins

CatecholEpicatechinCinnamicacidHypericinChrysinAbyssinoneTotarol

Ellagitannin

SubstratedeprivationMembranedisruption

Bindtoadhesins,complexwithcellwall,inactivateenzymesBindtoadhesins

ComplexwithcellwallInactivateenzymes

InhibitHIVreversetranscriptase?

BindtoproteinsBindtoadhesinsEnzymeinhibitionSubstratedeprivationComplexwithcellwallMembranedisruptionMetalioncomplexation

InteractionwitheucaryoticDNA(antiviralactivity)Membranedisruption

Intercalateintocellwalland/orDNABlockviralfusionoradsorptionFormdisulfidebridges?

17422666

58,114175,18232,219164122

196,210192

87,33,35

Coumarins

Terpenoids,essentialoilsAlkaloids

LectinsandpolypeptidesPolyacetylenes

WarfarinCapsaicinBerberinePiperine

Mannose-specificagglutininFabatin

8S-Heptadeca-2(Z),9(Z)-diene-4,6-diyne-1,8-diol

26,95,113,25142

15,34,73,94145,25362

(186,224).ThecatechinsinactivatedcholeratoxininVibrio(25)andinhibitedisolatedbacterialglucosyltransferasesinS.mutans(151),possiblyduetocomplexingactivitiesdescribedforquinonesabove.Thislatteractivitywasborneoutininvivotestsofconventionalrats.Whentheratswerefedadietcon-taining0.1%teacatechins,fissurecaries(causedbyS.mutans)wasreducedby40%(166).

Flavonoidcompoundsexhibitinhibitoryeffectsagainstmul-tipleviruses.Numerousstudieshavedocumentedtheeffec-tivenessofflavonoidssuchasswertifrancheside(172),glycyr-rhizin(fromlicorice)(242),andchrysin(48)againstHIV.Morethanonestudyhasfoundthatflavonederivativesareinhibitorytorespiratorysyncytialvirus(RSV)(21,111).Kauletal.(111)provideasummaryoftheactivitiesandmodesofactionofquercetin,naringin,hesperetin,andcatechinininvitrocellculturemonolayers.Whilenaringinwasnotinhibitorytoherpessimplexvirustype1(HSV-1),poliovirustype1,parainfluenzavirustype3,orRSV,theotherthreeflavonoidswereeffectiveinvariousways.Hesperetinreducedintracellu-larreplicationofallfourviruses;catechininhibitedinfectivitybutnotintracellularreplicationofRSVandHSV-1;andquer-cetinwasuniversallyeffectiveinreducinginfectivity.Theau-thorsproposethatsmallstructuraldifferencesinthecom-poundsarecriticaltotheiractivityandpointedoutanotheradvantageofmanyplantderivatives:theirlowtoxicpotential.TheaverageWesterndailydietcontainsapproximately1gofmixedflavonoids(124);pharmacologicallyactiveconcentra-tionsarenotlikelytobeharmfultohumanhosts.

AnisoflavonefoundinaWestAfricanlegume,alpinumi-soflavone,preventsschistosomalinfectionwhenappliedtopi-cally(175).Phloretin,foundincertainserovarsofapples,mayhaveactivityagainstavarietyofmicroorganisms(101).Galan-gin(3,5,7-trihydroxyflavone),derivedfromtheperennialherbHelichrysumaureonitens,seemstobeaparticularlyusefulcom-pound,sinceithasshownactivityagainstawiderangeofgram-positivebacteriaaswellasfungi(2)andviruses,inpar-ticularHSV-1andcoxsackieBvirustype1(145).

Delineationofthepossiblemechanismofactionofflavonesandflavonoidsishamperedbyconflictingfindings.Flavonoidslackinghydroxylgroupsontheir␤-ringsaremoreactiveagainstmicroorganismsthanarethosewiththeϪOHgroups(38);thisfindingsupportstheideathattheirmicrobialtargetisthemembrane.Lipophiliccompoundswouldbemoredisrup-tiveofthisstructure.However,severalauthorshavealsofoundtheoppositeeffect;i.e.,themorehydroxylation,thegreatertheantimicrobialactivity(189).Thislatterfindingreflectsthesim-ilarresultforsimplephenolics(seeabove).Itissafetosaythatthereisnoclearpredictabilityforthedegreeofhydroxylationandtoxicitytomicroorganisms.

Tannins.“Tannin”isageneraldescriptivenameforagroupofpolymericphenolicsubstancescapableoftanningleatherorprecipitatinggelatinfromsolution,apropertyknownasastrin-gency.Theirmolecularweightsrangefrom500to3,000(87),andtheyarefoundinalmosteveryplantpart:bark,wood,leaves,fruits,androots(192).Theyaredividedintotwogroups,hydrolyzableandcondensedtannins.Hydrolyzabletanninsarebasedongallicacid,usuallyasmultipleesterswithD-glucose,whilethemorenumerouscondensedtannins(oftencalledproanthocyanidins)arederivedfromflavonoidmono-mers(Fig.1).Tanninsmaybeformedbycondensationsofflavanderivativeswhichhavebeentransportedtowoodytis-suesofplants.Alternatively,tanninsmaybeformedbypoly-merizationofquinoneunits(76).Thisgroupofcompoundshasreceivedagreatdealofattentioninrecentyears,sinceitwassuggestedthattheconsumptionoftannin-containingbever-

570COWANCLIN.MICROBIOL.REV.

FIG.1.Structuresofcommonantimicrobialplantchemicals.

ages,especiallygreenteasandredwines,cancureorpreventavarietyofills(198).

Manyhumanphysiologicalactivities,suchasstimulationofphagocyticcells,host-mediatedtumoractivity,andawiderangeofanti-infectiveactions,havebeenassignedtotannins(87).Oneoftheirmolecularactionsistocomplexwithproteinsthroughso-callednonspecificforcessuchashydrogenbondingandhydrophobiceffects,aswellasbycovalentbondformation(87,210).Thus,theirmodeofantimicrobialaction,asde-scribedinthesectiononquinones(seeabove),mayberelatedtotheirabilitytoinactivatemicrobialadhesins,enzymes,cellenvelopetransportproteins,etc.Theyalsocomplexwithpoly-saccharide(247).Theantimicrobialsignificanceofthispartic-ularactivityhasnotbeenexplored.Thereisalsoevidencefor

VOL.12,1999ANTIMICROBIALPLANTCHEMICALS571

FIG.2.Reactionfortheconversionoftyrosinetoquinone.

directtionsniciosamodifyinactivationthemorphologyofmicroorganisms:ofgermtubeslowtanninofCrinipellisconcentra-disrupt(33).digestiveTanninseventsinplantsinruminalinhibitinsectgrowth(196)per-andninsScalbertinhibitoryin1991.(192)Hereviewedlisted33theantimicrobialanimals(35).

propertiesoftan-theseactivitiesoftanninsstudiesupwhichtothathadpoint.documentedAccordingthetoandbindbacteria.studies,tanninsCondensedcanbetanninstoxictohavefilamentousbeendeterminedfungi,yeasts,proteasecellninsactivitywallsof(105).ruminalAlthoughbacteria,thispreventingtoisgrowthandbioticarealatalightfoundactivityconsideredinofatleastpartiallyresponsiblestillspeculative,fortheanti-tan-Nepalmethanolic(221).ThisextractsactivityofthewasbarkenhancedofTerminaliabystudiesactivation(320to400nmat5W/m2for2h).AtleastUVtranscriptaseshaveshowntanninstobeinhibitorytoviralreversetwofusedCoumarins.(111,Coumarins155).

forbenzeneand␣-pyroneareringsphenolic(161).Theysubstancesareresponsiblemadeofbeentheantithromboticidentifiedcharacteristic(95).odorTheiroffamehay.Asof1996,atleast1,300hadtorymarin(152)activities.(223),Warfarinanti-inflammatoryhascomemainlyfromtheiris(177),andvasodila-estingly,whichisusedbothasanaoralparticularlyanticoagulantwell-knownand,inter-cou-effects(232)(24).asCoumarinsarodenticideare(113).knownIttobemayalsohaveantiviralcommunity.andthereforenouncedHowever,arehighlytoxicinrodentsrecenttreatedwithcautionbythemedicalinappearsvivoanimalspecies-dependentstudiesmetabolism”studieshave(244),shownsothata“pro-manyinthattoxiccoumarincannotderivativesbeextrapolatedmaybesafelytohumans.excretedItR.Severaltheurine1954,D.nantsoughtThornes,otherinhumansanagentworkingcoumarins(244).

toathaveantimicrobialproperties.treatthevaginalBostoncandidiasisLying-InHospitalinhispreg-inalbicanspatients.marin-spiked.(DuringCoumarinsubsequentwasfoundinvivoinvitrotoinhibitCandidaanimalspotentinwatersupplywasinadvertentlytestsonrabbits,giventotheallcou-thefailcontraceptivetheresearchagentfacilitywhenandbreedingwasdiscoveredprogramsstartedtobearophagesAs[225].)agroup,Itsestrogeniccoumarinseffectshavebeenwerefoundlaterdescribed(206).toinfections.(37),ventbutrecurrencesMorewhichofspecifically,couldhaveanindirecttonegativestimulateeffectmac-oncoldsorescoumarincausedbyhasHSV-1beeninusedhumanstopre-namicwasgram-positiveacids,foundrelatedineffectivetocoumarins,againstleprosyseemto(225).Hydroxycin-(24)droxylatedresponsederivativesbacteriaof(66).coumarins,Also,phytoalexins,beinhibitorytoareproducedwhicharehy-antifungaltoumentedall,inactivityfungalwoodruff(95).infectionandcanbepresumedincarrotstohavein(GaliumGeneralodoratumantimicrobial)extractsactivity(224).wasAlldoc-inscarce,datautilityalthoughaboutspecificmanyreportsantibioticgivepropertiesreasontoofcoumarinsaretherresearchmayresideiswarranted.

inthesephytochemicals(26,believe83,193).thatsomeFur-TerpenoidsandEssentialOils

essentia,Thefragranceofplantsiscarriedinthesocalledquintametabolitesorisoprenethatessentialarehighlyoilfraction.enrichedTheseincompoundsoilsarebasedsecondarygeneralpenes,welltriterpenes,chemicalstructurestructure(Fig.1).andtetraterpenesisTheyCarecalledterpenes,ontheiran10H16,and(Ctheyoccurasditer-20,compoundsashemiterpenes(CC30,andC40),as5)andsesquiterpenesarecontainadditionalelements,usually(C15oxygen,).WhentheythetheyTerpenoidstermedterpenoids.

acidssharetheirareoriginssynthesizedwithfattyfromacids.acetateTheyunits,andassuchExamplesinthat(monoterpenes)oftheycommoncontaindifferfromfattyterpenoidsextensivebranchingandarecyclized.noids).theArtemisinandanditsfarnesolderivativeandaremethanolandcamphor␣artemisin(sesquiterpe-1985,namethetheqinghaosu,findcurrentuse-arteether,asantimalarialsalsoknown(237).byIndrugWorldsteeringHealthcommitteeOrganizationofthedecidedscientifictodevelopworkingthegroupof22,Terpenenesasatreatmentorterpenoidsforcerebralaremalaria.

latteractiveagainstbacteria(4,8,213,82,237).221),90,121,144,197,220,221),fungi(18,84,122,179,180,ativesIn1977,virusesitwas(74,reported86,173,that212,246),andprotozoa(78,inhibitedexaminedtodatewereinhibitory60%oftoessentialfungiwhileoilderiv-30%onetoofseveralbacteriaterpenoids(39).The(seetriterpenoidbelow)whichbetulinichavebeenacidisjustfullyinhibitruptionunderstoodHIV.Thebutmechanismisofactionofterpenesshownisnotal.diterpenoids(144)byfoundthelipophilicspeculatedcompounds.toAccordingly,involvemembraneMendozadis-ettheirbyadditionthatincreasingofamethylthehydrophilicitygroupdrasticallyofkaurenereducedpenoidsantimicrobialcontrolpresentinactivity.essentialFoodoilsscientistsofplantshavetofoundtheter-ciallychlorineavailableofListeriamonocytogenes(16).Oilofbasil,beusefulacommer-intheindisinfectingherbal,waslettucefoundleavestobe(241).

aseffectiveas125ppmmanyChilethanMesoamericanpeppersareaculturesfooditem(44).foundTheirnearlyuseubiquitouslyinvitaminadesirefoundC,provitaminstoflavorfoods.Manyessentialnutrients,mayreflectsuchmoreaswideinchiles(27).AterpenoidAandE,constituent,andseveralcapsaicin,Bvitamins,arenervous,rangefindingcardiovascular,ofbiologicalandactivitiesdigestiveinhasasystemshumans,affectingthecrobialuseasananalgesic(47).Theevidence(236)foritsasantimi-wellasfoundalbicansthatactivitycapsaicinismixed.mightRecently,enhanceCichewiczthegrowthandThorpeofCandida(42)extents.butmucosa,Althoughthatitclearlypossiblyinhibiteddetrimentalvarioustobacteriathetodiffering(106).eroonianAnothercapsaicinhot-tastingisalsoditerpene,bactericidalaframodial,toHelicobacterhumangastricfrompyloriterpenoidTheethanol-solublespice,isabroad-spectrumfractionofpurpleantifungalaCam-prairie(18).

clovertivityagainstcalledBacilluspetalostemumol,subtilisandwhichStaphylococcusshowedexcellentyieldsaaureusand

ac-572COWANlesserdida(23)albicansactivity(100).againstTwogram-negativediterpenesisolatedbacteriaaswellasCan-againstwereCandidaStaphylococcusfoundtobebyBatistaetal.aureusmore,democratic;theyworkedwellthespp.WhenitwasobservedV.choleraethatresidents,P.aeruginosaofMali,usedandgastricbarktionsulcers,ofatreeinvestigatorscalledPtelopsistestedsuberosaterpenoid-containingforthetreatmentfrac-ofinduced.in10tionTheyratsfoundbeforethatandtheaftertheratshadulcerschemicallyWhetherofulcersprotectionthisactivityanddiminishedterpenoidspreventedtheforma-wastheseverityofexistentulcers.(108)ofthegastricmucosaduetoisnotantimicrobialclear(53).Kadotaactionoretal.toherb,foundcoulddirectlythattrichorabdalinhibitH.A,pyloriaditerpene.

fromaJapaneseAlkaloids

firstHeterocyclicnitrogencompoundsarecalledalkaloids.Theisolatedmedicallyusefulexampleofanalkaloidwasmorphine,(69);in1805fromtheopiumpoppyPapaversomniferumgodthenamemorphinecomesfromtheGreekMorpheus,morphine.ofdreams.CodeineandheroinarebothderivativesofplantsareofDiterpenoidalkaloids,commonlyisolatedfromtheSolamargine,commonlytheRanunculaceae,orbuttercup(107)family(15),sianumafoundglycoalkaloidtohaveantimicrobialproperties(163).tion,andotheralkaloidsmayfrombetheusefulberriesagainstofSolanumHIVinfec-kha-AIDS(142,biocidal(140).200)Whileaswellalkaloidsasintestinalhavebeeninfectionsfoundassociatedtowithciestheir[78]),effectsthe(includingmajorantidiarrhealagainstGiardiaeffectandisprobablyEntamoebahavemicro-spe-group.Berberineeffectsonistransitanimportanttimeintheduetorepresentativesmallintestine.

oftheplasmodiaItisplanar(163).potentiallyThemechanismeffectiveagainstofactiontrypanosomesalkaloidof(73)and(93)isattributedquaternarytoalkaloidstheirabilitysuchtointercalateasberberinehighlywithandaromaticDNAharmane(176).LectinsandPolypeptides

reportedPeptidescontaininwhich1942(19).areinhibitorytomicroorganismswerefirstbe(222,theformationdisulfidebondsTheyofion(253).arechannelsTheirofteninmechanismpositivelythemicrobialofchargedactionmembranemayandproteins253)orcompetitiveinhibitionofadhesionofmicrobialestlectins,hasbeentohostfocusedpolysaccharidemostlyonstudyingreceptorsanti-HIV(202).Recentpeptidesinter-andromolecules,butthehassuchinhibitionasthatoffrombacteriatheherbaceousandfungibyAmaranthusthesemac-andThioninslongbeen,toconsistareknownofpeptides(50).

commonlyfoundinbarleyandwheatThioninsyeastsand47gram-negativeaminoacidresiduesandgram-positive(45,143).Theybacteriaaretoxic(65).fungiresiduebutAX1notbacteriaandAX2(118).fromFabatin,sugarbeetanewlyareactiveagainstrelatednosatopeptide␥-thioninsfromfromfavagrainsbeans,andappearstobeidentifiedstructurally47-ces(253).

,andEnterococcushiraebutnotinhibitsCandidaE.orcoliSaccharomy-,P.aerugi-lectinsThelargerlectinmolecules,whichincludemannose-specific(128),fromseveralplants(20),MAP30frombittermelon(64),rus),areGAP31fromGeloniummultiflorum(28),andjacalincellprobablyinhibitorybytoviralproliferation(HIV,cytomegalovi-compoundscomponents.inhibitinginhibitadhesionsuchItviralinteractionwithcriticalhostwillasistheseworthemphasizingthatmoleculesandnotbewhosedetectedmodebyofusingactionmostmaygeneral

betoCLIN.MICROBIOL.REV.

plantsay-guidedantimicrobialscreeningprotocols,evenwiththebioas-ral-productsfractionationmacologychemists(seeproceduresbelow).It(131,isan181)areausedofethnophar-bynatu-potentiallywhichdeservesattention,sothatinitialscreensofences25,43,pharmacologicallyand238)maybeactivemadeplantsmore(describeduseful.

inrefer-Mixtures

oralThechewingstickiswidelyusedinAfricancountriesasstickshygienestickcomefromaid(indifferentplacespeciesofatoothbrush)anofplants,(156).Chewing(5).deiaCrudethechemicallyextractsofactiveonespeciescomponentusedmaybeandheterogeneouswithinoneromonaswerneckei(183).gingivalis,inhibitedandBacteroidestheperiodontalforthispurpose,Serin-melaninogenicuspathogensinPorphy-(loidsFagaraThezanthoxyloidesactivecomponent)wasfoundofthetoNigerianconsistofchewingvitrostickoping(157).known.

countries,Whethermightthesefindcompounds,useintheWesternlongutilizedvariousworldisinnotdevel-alka-yetlatex,Papaya(Caricapapaya)yieldsamilkysap,oftencalledathemwhichalkaloid,ispapain,isacomplexawell-knownmixtureproteolyticofchemicals.enzymeChief(162).amongpresent(224).andcarpaine,maycontributeisalsopresenttoits(34).antimicrobialTerpenoidspropertiesarealsoAnB.ylococcussubtilisOsato,Enterobacteretal.(168)cloacaefound,thelatextobebacteriostatictounknownAyurvedaaureusE.coli,Salmonellatyphi,Staph-isa,typeandofProteushealingvulgariscraftpracticed.

inIndiabutnotplantintheUnitedStates.Ayurvedicpractitionersrelyonformulations.extracts,bothAshwagandhaThe“pure”single-plantpreparationsandmixedmixture)(Withaniapreparationssomniferahavelyricalnames,suchasusedtheirtotreat(133),animalsandLivo-vetroot)(54),Cauvery100(aas(125).Thesepreparationsareantidiarrhealantimicrobialwellashumans(125).Inadditionto(59),(134),activities,theyhavebeenfoundtohaveAbana,andexperimentallyanpsychotropicimmunomodulatoryAyurvedicformulation,(201)properties.(54,133),anticancerfoundInvivostudiesofmicroorganismsinducedactivityagainstcardiacwhicharrhythmiasaslightAyurvedicpreparationsindogsreduction(75).inhaveTwo(170).areAspergillusspp.(54)andPropionibacteriumacnesvivo,(TheaspergillosisstudywasperformedwithmiceineffectsandwholeareitdueisthereforetothestimulationimpossibleofmacrophagetodetermineactivitywhethertheofTheanimaltoxicityratherofAyurvedicthantopreparationsdirectantimicrobialinthehasbeeneffects.)

themetals.somebloodPrpic-Majicspeculation,etespeciallyal.identifiedsincehighsomelevelsofofthemsubjectleadincludeAyurvedicofadultvolunteerswhohadself-medicatedintheisPropolismedicinestrees.oftencalledisacrude(178).

withbeeglue,extractsinceofhoneybeesthebalsamgatherofvariousitfromtrees;theitdescribedItschemicalbenzoicabove,terpenoidscompositionareispresent,verycomplex:aswelllikeasthelatexesesterspropolis,(9).acidsSyntheticandesters,cinnamicandsubstitutedacids,identicalphenolicflavonoids,tothoseacidsandinfluenzawereactivevirusfound(199).toAmorosinhibitethemagglutinational.foundthatpropolisactivityfromofvirusturestypeagainst2,vesicularanacyclovir-resistantstomatitisvirus,mutantandpoliovirusofHSV-1,(9).adeno-wasactweresynergistically.ofchemicals,Whilesuchastheareflavonefoundinlatexandpropolis,Mix-mayincubatedactivesimultaneouslyinisolationagainstwiththeHSV-1,andflavonolcomponentsvirusweremultiplemoreflavonoidseffective

VOL.12,1999ANTIMICROBIALPLANTCHEMICALS

TABLE3.Solventsusedforactivecomponentextractiona573

WaterEthanolMethanolChloroformDichloromethanolEtherAcetone

Anthocyanins(111)Starches

Tannins(192)Saponins(53)TerpenoidsPolypeptidesLectins

Tannins(204)Polyphenols(151)

Polyacetylenes(29,62)Flavonol(29,100)Terpenoids(82)Sterols(53)Alkaloids(103)Propolis

AnthocyaninsTerpenoids(221)Saponins

Tannins(221)XanthoxyllinesTotarol(121)

Quassinoids(115)Lactones(180)Flavones(189,219)Phenones(174)Polyphenols(235)

Terpenoids(18)Flavonoids(175)

Terpenoids(144)

AlkaloidsTerpenoidsCoumarinsFattyacids

Flavonols(2)

aCompoundsinboldarecommonlyobtainedonlyinonesolvent.Referencesaregiveninparentheses.

thansinglechemicals,apossibleexplanationofwhypropolisismoreeffectivethanitsindividualcompounds(10).Ofcourse,mixturesaremorelikelytocontaintoxicconstituents,andtheymustbethoroughlyinvestigatedandstandardizedbeforeap-provedforuseonalarge-scalebasisintheWest.

OtherCompounds

Manyphytochemicalsnotmentionedabovehavebeenfoundtoexertantimicrobialproperties.Thisreviewhasattemptedtofocusonreportsofchemicalswhicharefoundinmultipleinstancestobeactive.Itshouldbementioned,however,thattherearereportsofantimicrobialpropertiesassociatedwithpolyamines(inparticularspermidine)(70),isothiocyanates(57,104),thiosulfinates(215),andglucosides(149,184).

Polyacetylenesdeservespecialmention.Estevez-Braunetal.isolatedaC17polyacetylenecompoundfromBupleurumsalici-folium,aplantnativetotheCanaryIslands.Thecompound,8S-heptadeca-2(Z),9(Z)-diene-4,6-diyne-1,8-diol,wasinhibi-torytoS.aureusandB.subtilisbutnottogram-negativebac-teriaoryeasts(62).AcetylenecompoundsandflavonoidsfromplantstraditionallyusedinBrazilfortreatmentofmalariafeverandliverdisordershavealsobeenassociatedwithanti-malarialactivity(29).

Muchhasbeenwrittenabouttheantimicrobialeffectsofcranberryjuice.Historically,womenhavebeentoldtodrinkthejuiceinordertopreventandevencureurinarytractinfec-tions.Intheearly1990s,researchersfoundthatthemonosac-charidefructosepresentincranberryandblueberryjuicescompetitivelyinhibitedtheadsorptionofpathogenicE.colitourinarytractepithelialcells,actingasananalogueformannose(252).Clinicalstudieshaveborneouttheprotectiveeffectsofcranberryjuice(17).Manyfruitscontainfructose,however,andresearchersarenowseekingasecondactivecompoundfromcranberryjuicewhichcontributestotheantimicrobialpropertiesofthisjuice(252).

EXPERIMENTALAPPROACHES

ExtractionMethods

Adviceaboundsfortheamateurherbalistonhowtopreparehealingcompoundsfromplantsandherbs.Waterisalmostuniversallythesolventusedtoextractactivity.Athome,driedplantscanbeingestedasteas(plantssteepedinhotwater)or,rarely,tinctures(plantsinalcoholicsolutions)orinhaledviasteamfromboilingsuspensionsoftheparts.Driedplantpartscanbeaddedtooilsorpetroleumjellyandappliedexternally.Poulticescanalsobemadefromconcentratedteasortinctures(30,224).Scientificanalysisofplantcomponentsfollowsalogicalpathway.Plantsarecollectedeitherrandomlyorbyfollowingleadssuppliedbylocalhealersingeographicalareaswheretheplantsarefound(135).Initialscreeningsofplantsforpossibleantimicrobialactivitiestypicallybeginbyusingcrudeaqueousoralcoholextractionsandcanbefollowedbyvariousorganicextractionmethods.Sincenearlyalloftheidentifiedcompo-nentsfromplantsactiveagainstmicroorganismsarearomaticorsaturatedorganiccompounds,theyaremostoftenobtainedthroughinitialethanolormethanolextraction.Infact,manystudiesavoidtheuseofaqueousfractionationaltogether.Theexceptionalwater-solublecompounds,suchaspolysaccharides(e.g.,starch)andpolypeptides,includingfabatin(253)andvariouslectins,arecommonlymoreeffectiveasinhibitorsofpathogen(usuallyvirus)adsorptionandwouldnotbeidenti-fiedinthescreeningtechniquescommonlyused.Occasionallytanninsandterpenoidswillbefoundintheaqueousphase,buttheyaremoreoftenobtainedbytreatmentwithlesspolarsolvents.Table3listsexamplesofextractionsolventsandtheresultantactivefractionsreportedinrecentstudies.Com-poundswhich,accordingtotheliterature,partitionexclusivelyinparticularsolventsareindicatedinboldfacetypeinthetable.

Anypartoftheplantmaycontainactivecomponents.Forinstance,therootsofginsengplantscontaintheactivesa-poninsandessentialoils,whileeucalyptusleavesareharvestedfortheiressentialoilsandtannins.Sometrees,suchasthebalsampoplar,yieldusefulsubstancesintheirbark,leaves,andshoots(224).

Foralcoholicextractions,plantpartsaredried,groundtoafinetexture,andthensoakedinmethanolorethanolforex-tendedperiods.Theslurryisthenfilteredandwashed,afterwhichitmaybedriedunderreducedpressureandredissolvedinthealcoholtoadeterminedconcentration.Whenwaterisusedforextractions,plantsaregenerallysoakedindistilledwater,blotteddry,madeintoaslurrythroughblending,andthenstrainedorfiltered.Thefiltratecanbecentrifuged(ap-proximately20,000ϫg,for30min)multipletimesforclarifi-cation(42,221).Crudeproductscanthenbeusedindiscdiffusionandbrothdilutionassaystotestforantifungalandantibacterialpropertiesandinavarietyofassaystoscreenforantiviralactivity,asdescribedbelow.

Natural-productschemistsfurtherpurifyactivechemicalsfromcrudeextractsbyavarietyofmethods.Petalostemumol,aflavanolfrompurpleprairieclover,wasobtainedfromtheethanolextractbypartitioningbetweenethylacetateandwa-ter,followedbypartitioningbetweenn-hexaneand10%meth-anol.Themethanolfractionwaschromatographedandelutedwithtoluene(100).Terpenoidlactoneshavebeenobtainedby

574COWANCLIN.MICROBIOL.REV.

TABLE4.Comparisonofextractantsondifferentparametersbasedonafive-pointscale(1to5)andwithdifferentweights

allocatedtothedifferentparametersaParameter

Weight

bAcetoneAdCeEthanolA

C

MethanolA

C

A

MCWcC

MethylenedichlorideA

C

A

Water

C

QuantityextractedRateofextraction

No.ofcompoundsextractedNo.ofinhibitorsextractedToxicityinbioassayEaseofremovalHazardoustouseTotal

ab3355452

61220201620810231520201620810291210085852612151085864121215200102711212201501027112121020810678121215208106833151020820679315151582067999501608479950160847

Reprintedfromreference61withpermissionofthepublisher.

Five-pointscale(5,best;1,worst),basedonEloff’s(61)judgmentoftheimportanceoftheparameter.cMCW,methanol-chloroform-water.dResultsforAnthocleistagrandiflora.eResultsforCombretumerythrophyllum.

successiveextractionsofdriedbarkwithhexane,CHCl3,andmethanol,withactivityconcentratingintheCHCl3fraction(180).Thechemicalstructuresofthepurifiedmaterialcanthenbeanalyzed.Techniquesforfurtherchemicalanalysisincludechromatography,bioautography,radioimmunoassay,variousmethodsofstructureidentification,andnewertoolssuchasfastatombombardmentmassspectrometry,tandemmassspectroscopy(181),high-performanceliquidchromatog-raphy,capillaryzoneelectrophoresis,nuclearmagneticreso-nancespectroscopy,andX-raycystallography(25).

Recently,Eloff(61)examinedavarietyofextractantsfortheirabilitytosolubilizeantimicrobialsfromplants,aswellasotherfactorssuchastheirrelativerankingasbiohazardsandtheeaseofremovalofsolventfromthefraction.Thefocusofthestudywastoprovideamorestandardizedextractionmethodforthewidevarietyofresearchersworkingindiversesettings.Althoughitisnotoneofthemorefrequentlyusedextractantsinstudiespublishedtodate,acetonereceivedthehighestoverallrating.Infact,inareviewof48articlesdescrib-ingthescreeningofplantextractsforantimicrobialpropertiesinthemostrecentyearsoftheJournalofNaturalProducts,theJournalofEthnopharmacology,andtheInternationalJournalofPharmacognosy,onlyonestudyusedacetoneasanextractant.OfthesolventslistedinTable3,whicharereportedintherecentliteraturewiththehighestfrequency,Eloffrankedthemintheordermethylenedichloride,methanol,ethanol,andwa-ter.Table4displaysthebreakdownofscoresforthevarioussolventsstudied.Therowindicatingthenumberofinhibitorsextractedwitheachsolventpointstotwoimplications:first,thatmostactivecomponentsarenotwatersoluble,supportingthedatareportedinTable3,andsecond,thatthemostcom-monlyusedsolvents(ethanolandmethanol,bothusedasini-tialextractantsinapproximately35%ofthestudiesappearingintherecentliterature)maynotdemonstratethegreatestsensitivityinyieldingantimicrobialchemicalsonaninitialscreening.Thisdisparityshouldbeexaminedasthesearchfornewantimicrobialsintensifies.

Efficacy

Invitroexperiments.(i)Bacteriaandfungi.Initialscreeningofpotentialantibacterialandantifungalcompoundsfromplantsmaybeperformedwithpuresubstances(2,23,117)orcrudeextracts(73,203,182).Themethodsusedforthetwotypesoforganismsaresimilar.Thetwomostcommonlyusedscreenstodetermineantimicrobialsusceptibilityarethebrothdilutionassay(18,89,219)andthediscoragarwelldiffusionassay(153);clinicalmicrobiologistsareveryfamiliarwiththeseassays.Adaptationssuchastheagaroverlaymethod(138)mayalsobeused.Insomecases,theinoculatedplatesortubesareexposedtoUVlight(221)toscreenforthepresenceoflight-sensitizingphotochemicals.Othervariationsofthesemethodsarealsoused.Forinstance,totesttheeffectsofextractsoninvasiveShigellaspecies,noncytotoxicconcentrationsoftheextractscanbeaddedtoVerocellculturesexposedtoaShi-gellainoculum(235).Thedecreaseincytopathiceffectinthepresenceoftheplantextractisthenmeasured.

Inadditiontotheseassays,antifungalphytochemicalscanbeanalyzedbyasporegerminationassay.Samplesofplantex-tractsorpurecompoundscanbeaddedtofungalsporescol-lectedfromsolidcultures,placedonglassslides,andincubatedatanappropriatetemperature(usually25°C)for24h.Slidesarethenfixedinlactophenol-cottonblueandobservedmicro-scopicallyforsporegermination(179).

Ofcourse,afterinitialscreeningofphytochemicals,moredetailedstudiesoftheirantibioticeffectsshouldbeconducted.Atthisstage,morespecificmediacanbeusedandMICscanbeeffectivelycomparedtothoseofawiderrangeofcurrentlyusedantibiotics.Theinvestigationofplantextractseffectiveagainstmethicillin-resistantS.aureus(190,229)providesanexampleofprospectingfornewcompoundswhichmaybeparticularlyeffectiveagainstinfectionsthatarecurrentlydiffi-culttotreat.Satoetal.(190)examinedtheactivityofthreeextractsfromthefruitingbodiesofthetreeTerminaliachebulaRETSagainstmethicillin-sensitiveandmethicillin-resistantS.aureusaswellas12othergram-negativeandgram-positivebacteria.TheyfoundthatgallicacidderivativesweremoreeffectiveagainstbothtypesofS.aureusthantheywereagainstotherspecies.

(ii)Viruses.Severalmethodsareavailabletodetecteithervirucidalorinhibitory(antiviral)plantactivity.Investigatorscanlookforcytopathiceffectsorplaqueformation(1,111)orfortransformationorproliferativeeffectsoncelllines(48).ViralreplicationmaybeassayedbydetectionofviralproductssuchasDNA,RNA,orpolypeptides(127,171).VlietinckandVandenBerghe(238)havenotedthatthemethodforassayingantiviralsubstancesusedinvariouslaboratoriesisnotstan-dardized,andthereforetheresultsareoftennotcomparabletooneanother.Theseauthorsalsopointoutthatresearchersmustdistinguishbetweenmerelytoxiceffectsofagentsonhost

VOL.12,1999cellslistsvariousandtrueantiviralpropertiesoftheplantextracts.Table5screenItshouldinmicroorganismforactivebevitromentionedantiviralscreeningassays.

substancesherewhichthatantiviralassaysoftenscreeningstances.procedurestohostforcells;antibacterialthispreventactivityadsorptionoftheandisantifungaloverlookedinantiadhesiveHowever,thelargebodyofliteratureaccumulatingsub-thatinphytochemicalsapproachesshouldtobacterialbeassessedinfectionsforthis(109)classofsuggestsonactionactivity(iii)additionProtozoatotheirkillingandinhibitoryactivities.

catedviruses.thanagainstscreeningprotozoaandhelminths.Screeningplantextractsforforandhelminthscanbemorecompli-fewertheorganismsGrowingaretheobtained.organismsactivityagainstbacteria,fungi,orAssaysisoftenmoredifficult,andtwomicroorganism.TrypanosomamethodstoassayForinstance,compoundsFreiburghausaregenerallyspecificforforetal.(73)usedsomesthenwereexposedbrucei.First,tovarious66-hconcentrationstissuecultureseffectivenessofthetrypano-against(Inofthisthecase,MICsthewereMICdeterminedwasdefinedwithaninvertedofextracts,microscope.andpanosomes.)extractwhichofSecond,completelytheseauthorsinhibitedasthelowestconcentrationusedthegrowthofthetry-anti-infectiveTheretrypanosomeisgreatviabilityinterestininmicrotiterplantchemicalswells.

afluorescenceassaywhichmayhavefordiolabelledtestingextractspropertieswhichformayPlasmodiumbetoxictospecies.plasmodiaOneusesmethodra-withbatedmicrotitermicroorganismsinanerythrocyteinfectionassayPlasmodiumwithanddisheswithout(72).Parasitizederythrocytesareincu-titated.growthAnotherorganismslaboratoryaftertestsubstances,andthenumbersofdirectlytheincubationmeasuresperiodarequan-animalInvivoofPlasmodiumtestingofphytochemicals.undertheinfluencedecreasesintheTwooftheextracts(29).of(186)theeffectsstudiesoffromoolongthetearecentliteratureareprimetheexamplesdescriptionsofbacterialandmicinfectioncholerapolyphenolsondentalcariesinratsmodel,inmiceP.(226)(discussedabove).Anotherginseng.rats,terialTreatedwasusedaeruginosalunginfectionofathy-ratstohadtestdecreasedsubcutaneousadministrationsoftobeload,atleastalthoughpartiallyenhancedresponsiblehumorallungpathologyandbac-(207).

immunitywasthoughtpharmaceuticalsPerhapsbecauseofthelong-standinginterestinalternativetheforuseindevelopingandtropicalregionsoftheworld,centantiprotozoalmanyofeffectivenesstheinvivostudiesofplanttoextractsdatehave(55).examinedTwotoandteststudiestheeffectivenesswithratsusedofexperimentalacrudeIndianEntamoebaherbalextractinfectionsre-containingofanethanolicroformthealkaloidextractpiperineofPiper(78).Afterlongum(205)applyingfruits,probablytheskinestablishmentofextractmice,Perrettofthelegumeetal.(175)Milletiathonningiitopicallytochlo-theThereofarealsoofanimalsubsequentstudiesofSchistosomafoundthatitpreventedthetheactivitymansoniinfection.latexthepolygyrusagainstbarkofPteleopsisinfectionssuberosaofvariousextractswiththeagainstulcers(53),ofpapayaagainst(191),andofSantolinachamaecyparissushelminthHeligmosomoidesessentialorallyAnAyurvediccandidalinfectionsformulation,(213).

oilCauvery100,castortotheoil.ratsWhileeitherthisbeforetrialdidorafterdiarrheawaswasadministeredinducedbylosspreparationprotectiveinthesickbut,rather,itsnoteffecttestantimicrobialongutmotilityactivitiesandionofwithandanimals,acurativeitshowedeffectinthatratsCauvery(134).A100hadbothainducedsimilarulcersresults(133).wasTheperformedAyurvedicAshwagandhaonratswithsimilarchemicallystudywasfound

ANTIMICROBIALPLANTCHEMICALS575

TABLE5.InvitroantiviralscreeningassaysaDeterminationI.compoundInculturedcellsofviralduringinfectivityvirusmultiplicationundertwoconditions:

intheII.(A-S)oramixtureofcompounds,e.g.,plantpresenceextractsofasingleofcompoundsAfterextracellular(V-M).

incubationwithasinglecompound(V-S)or(A-M).

amixturePlaqueTitersuitableinhibitioncellassay(onlyforviruseswhichformplaquesin

Applicability:ofadeterminationsystems)

nontoxicofalimitednumberofvirusesinthepresenceA-SdoseofthetestsubstancePlaquereductionassay(onlyforvirusesTitersuitableactiondeterminationcellsystems)

whichformplaquesin

ofresidualvirusinfectivityafterextracellularcytotoxicity)

oftestsubstance(s)(seereferenceforcommentsonInhibitionApplicability:V-S,V-M

cytopathicofvirus-inducedeffectbutcytopathicdonotreadilyeffectform(forplaquesvirusesthatininduce

Determinationcultures)

cellmonolayersdoseofvirus,culturedofvirus-inducedcytopathiceffectincell

andtreatedinliquidwithmedium,anontoxicinfecteddoseofwiththealimitedApplicability:substance(s)

testA-S,A-MVirusDeterminationyieldreductiongivenamountofassay

ofthevirusvirusandyieldtreatedintissueswithaculturesnontoxicinfecteddoseofwiththeaVirustestthetitersubstance(s)

plaquedeterminationtestorthe50%carriedtissueoutcultureaftervirusinfectivemultiplicationdoseend-byApplicability:pointtest

A-S,A-MEnd-pointDeterminationtiterdeterminationofvirustitertechnique

reductionThisdilutionsmethodofinthepresenceoftwofoldespeciallytestcompound(s)

designedforApplicability:crudeextractsA-S,(238)theantiviralscreeningofA-MAssaysproductsbasedon(formeasurementvirusesthatofdospecializednotinducefunctionscytopathicandeffectsviral

orDeterminationformplaquesandtransformationhemadsorptionofvirusincellspecificcultures)

parameters,e.g.,hemagglutinationdetectingantiviral(Epstein-Barrtests(myxoviruses),inhibitionofcellantigensinvirus),immunologicaltests

Applicability:HIV,HSV,cytomegalovirus)cellcultures(Epstein-Barrvirus,ReductionpolypeptidesorA-S,inhibitionA-M,V-S,V-M

determinationininfectedofthecellsynthesiscultures,e.g.,ofvirusviralspecific

nucleicApplicability:precursorsorA-S,viraloftheA-M,genomeuptakeV-S,copyofradioactiveacids,V-M

numbersisotope-labelledaReprintedfromreference238withpermissionofthepublisher.

toAspergillusprolongmacrophage,theansurvivaleffectbelievedperiodoftoBALB/cbemediatedmiceinfectedbyincreasedwithforClinicaltrialsfunctioninhumans.(54).

Ofincenturiestotreatinfectionscourse,andotherplantsillnesseshaveinbeenusedInaboriginaltrainedsomecases,groups,traditionalbutcontrolledclinicalstudiesarehumansscarce.effectivenessscientistshavebegunkeepinghealersrecordsworkingoftogetherthesafetywithanderallyuncontrolledofphytochemicalandunrandomizedtreatments,studies.buttheseExamplesaregen-of

576COWAN

TABLE6.Compoundswithanti-HIVactivity

Target

Compound

Class

Plant

CLIN.MICROBIOL.REV.

Reference(s)

Reversetranscriptase

Ellagitannin

Hydroxymaprounicacid,hydroxybenzoate

Betulinicacid,platanicacidCatechin

Faicalein,quercetin,myricetin,baicalinNigranoicacid

Amentoflavone,scutellarein,others

BenzophenanthridineProtoberberinePsychotrinesMichellamineBSuksdorfinCoriandrinCaffeicacid

Cornusin,others

SwertifranchesideSalaspermicacidGlycyrrhizin—

Methylnordihydroguaiareticacid

Thujapolysaccharide

TanninTerpenoidsTerpenoidsPolyphenolFlavonoids

Terpenoids

Flavonoids,flavonesAlkaloidAlkaloidAlkaloidsAlkaloidCoumarinsCoumarinTannin

Condensedandhydro-lyzabletanninsFlavonoidFlavonoidFlavonoidProteinLignan

Polysaccharide

Lignin-polysaccharidecomplexesFlavonoids,flavonesProteinsLectinsTerpenoidTerpenoidFlavonoid

TerpenoidTerpenoids

Flavonoids,flavonesLectinsAlkaloid

PolysaccharideLectins

—aMaprouneaafricanaSyzigiumclaviflorum—

Quercusrubra,othersSchisandrasphaerandra—

——

Ipecac(Cephaelisipecacuanha)AncistrocladuskorupensisLomatiumsuksdorfii

Coriander(Coriandrumsativum)Hyssopofficinalis

CornusofficinalisandothersSwertiafranchetianaTrypterygiumwilfordii

Licorice(Glycyrrhizarhiza)Cactus(Opuntiastreptacantha)Manytrees

Thujaoccidentalis

Japanesewhitepine(Pinusparvifloria)—

Momordicacharantia,Geloniummultiflorum——

Turmeric(Curcumalonga)Quercusrubra

Rosemary(Rosmarinusofficinalis)Geumjaponicum

Snowdrop(Galanthus),daffodil(Narcissus),amaryllis(Amaryllis),Gerardia

SchumanniophytonmagnificumPrunella

Cymbidiumhybrid,Epiactichellebo-rine,Listeriaovata,UrticadioicaVarioustrees

AncistrocladuskorupensisHyssopofficinalis

ChrysanthemummorifoliumPokeweed(Phytolacca)

St.John’swort(Hypericum)?

CucurbitaceaefamilyPrunellavulgarisViolayedoensis

?

PanaxzingiberensisWuetFengAsteraceae

ChrysanthemummorifoliumHouttuyniacordata

155173

74147

165,208,216212

96,146,164,165,208,217,218200,2172172171421269911911117240

102,24238016012632,67

97,128–130206813967171246

32,48,671489424920

Integrase

—

MAP30,GAP31,DAP32,DAP30—

CaffeicacidCurcuminQuercetinCarnosolicacidUrsolicacid

Mannose-specificlectinsSchumannificine1Prunellin

Protease

Adsorption

Viralfusion

Mannose-andN-acetyl-glucosamine-specificlectinsPropolis

MichellamineBMAR-10Chrysin

29,000-mol-wtproteinHypericinCamptothecin

Trichosanthin,momor-charins——

Jacalin

ZingibrosideR-1ThiarubrinesChrysin—

Syncytiumformation

MixtureAlkaloid

PolysaccharideFlavone

Protein

AnthraquinoneAlkaloid

Ribosome-inactivingproteinsSulfatedpolysaccharideSulfonatedpolysaccha-rideLectinTerpenoidTerpenoidsFlavonoid

Essentialoil/terpenoids

9,5214281484141,9916914121415446,6486989688

Interferencewithcellularfactors

Unknown

a—,unspecified.

VOL.12,1999peer-reviewedarebrieflytrialsoftheuseofphytochemicalsinhumansizedAcross-sectionalreportedbrushestrial)oftheeffectivenessepidemiologicalhere.

ofchewingstudy(thus,notarandom-Africa.chewing-stickTheinpromotingstudy’sauthorsoralhygienesticksversustooth-foundwasconductedinWestcludedthethattheusersantimicrobialcomparedchemicalstotoothbrushareducedeffectivenessusersandcon-inoralsticksaddednooralhealthbenefitknown(156).toAlso,bepresentregardinginhavehealth,Mouthrinsesbeenevaluatedmouthrinsescontainingvariousantimicrobialsascontaininginhumansphytochemicals(reviewedinreference240).ListerineeffectiveorindecreasingplaqueorclinicalweregingivitisnotfoundastowerebealsToofhavedate,beenfewchlorhexidine.

performed.randomizedGironclinicaletal.trialsofplantantimicrobi-suppositories,SolanumnigrescensThelong-recognizedextractprovedinwomenwithnystatin,both(79)givencomparedasintravaginalanextracttobewithasefficaciousconfirmedasC.nystatin.albicansInvaginitis.1996thefectionsprovidedwerestudiedeffectsinofagroupcranberryofelderlyjuiceonurinarytractin-womengrouphadbyfewertheauthorwomen.Nodataarebacteriaaboutintheirclinicalurineoutcomes,thandidthebutuntreatedtreatedplaceboFour(17).

differentAyurvedicformulationsweretestedagainstformulations,fortheirreductionSundereffectivenessVati,producedagainstacneasignificantlyvulgaris.Oneoftheaplacebo.prietaryNointoxiclesionsidecounteffectsthandidtheotherthreeandgreaterthethetopicaltreatmentcompoundsofrespiratoryderivedfromweretropicalobservedplants,(170).Provir,Twopro-for(114).antiherpesagent,wereviraltestedinfections,inclinicalandtrialsVirend,in1994aestablishedSinceinthen,phasetheIIefficacystudiesand(167).

safetyofVirendhavebeenPLANTSIMMUNODEFICIENCYWITHEFFICACYAGAINSTVIRUSHUMAN

andEffectiveexamplewide,therapiesforHIVinfectionarebeingsoughtfarstudied.ofininthevivonaturalanti-HIVworldstudies,aswellasinlaboratories.Asonelicorice),Glycyrrhizin,14streptacanthato17extendedfoundinGlycyrrhizainfectionplantsinmice(thesourcehasbeenofweeks(242).thelifeAcrudeoftheextractretrovirus-infectedofthemicefromstudiestractperformedhadmarkedinmice,antiviralhorses,effectsandinvitro,cactusandOpuntiatoxicitytoThetoscopebesafehumansfoundtheex-of(3).

studiesofanti-HIVplantextractsrizeshandleindetailinthepresentreview,butTableistoo6summa-broadpurportedmanytoseveralusefultargetsofthecompoundsreviewsofaction.(36,Thestudied155,interestedtodateaswellastheir172,217).

readerisreferredCOMMERCIALSAFETYOFAVAILABILITYCOMPOUNDS

AND

compoundsAwidevarietyscriptionareavailableofplantinextracts,theUnitedmixtures,Statesandsingleplantexample,throughandpreparationshealthoffoodflavonesstoreswithoutapre-(brandandvitaminretailers.ForCapsaicinCitrusmainstreamappearsBioflavonoids)inatopicalareantiarthritissoldbysupplementnamesFlavonssuppliers.500preparationsgroceryrationsarerelativelyanddrugunregulated.stores.ThecreamavailableinThisover-the-counterresultsinManyofstoresuncertainalsosellandwholevariabledriedpurity.

prepa-plants,whichhavebeen

ANTIMICROBIALPLANTCHEMICALS577

foundtrousbyconsequences.occasionallytoObviously,bemisidentified,manywithpotentiallydisas-thethetheDietaryconsumerinhomegardens.Inplants1994,canCongressalsobepassedgrownquirementsFoodandSupplementHealthEducationAct,whichrequireddientsspecificallyDrugAdministrationtodeveloplabelingre-plementsuchproductstheasvitamins,designedminerals,forandproductsherbscontainingintendedtoingre-sup-“Supplementtobediet.labeledThenewasarules,dietaryissuedsupplementinlate1997,requiretritionalsoFacts”Facts”panelspanelappearingwithinformationandcarryaonsimilartothe“Nu-specifyrequirethepartthatofproductsprocessedfoods.TherulestheplantcontainingbotanicalingredientsplementsTheFood(63).asfoods,andDrugaslongAdministrationused(71).

asnoregulatesdietarysup-areetarytheOtherdrugclaimsaremadeforthemAmericanorganizationsoverseeingherbalsandbotanicalsScienceSupplementDieteticAlliance(12).

Labels(11)Association’sandtheFoodCommissionandNutritiononDi-pharmaceuticals,Thefirstinvestigationalnewdrugapplicationforherbal1997toticalmarket”(13).Whetheravailablebyprescription,wassubmittedinisunclear.thisSomeistheanalystsbeginningsuggestofasubstantialthat“rushsincecompanies(49).itisstillunclearwillnotwhetherinvestindrugtestingforpharmaceu-botanicalsthatbymostRichardnovelvandenBroek,industryproprietaryanalyst,claimsconcurs,canbesayingmadeablePlantsbiotechnologyantibioticresearchisbeingconductedinsteadand/orplantcompaniescomponents(7).

whicharecurrentlyarealsoamongtoconsumersthoselistedassupplementsinTable1.throughRoughcommercialoutletsavail-apeuticprovided.poisonsfoodstuffsIthasmaylongbeenrecognizedtoxicitythatpossiblyrankingsther-arearewithbestinalsocontainsubstanceswhichactastheseadvisedhumans(132).Clinicalscientistsandpractitionersproductstobeandawaretoconsiderofthewidespreadtheireffectsself-medicationonpatients.

CONCLUSIONSANDFUTUREDIRECTIONSwithScientistsgencyaneyefromtotheirdivergentfieldsareinvestigatingplantsanewcontinues.accompaniestheantimicrobialsearchastheusefulness.paceofspeciesAsenseextinctionofur-sandstypesofphytochemicalsLaboratoriesofwhichtheworldhavehaveinhibitoryfoundliterallyeffectsonthou-allshouldoftheirbemicroorganismssubjectedtoanimalinvitro.andhumanMoreofstudiesthesecompoundsticulareffectivenessontoxicitystudiesinwhole-organismaswellasansystems,includingtodetermineinpar-standardizebeneficialthemethodsnormalmicrobiota.examinationoftheireffectsofextractionItandwouldinvitrobeadvantageoustestingsothattoresultssearchcouldbemoresystematicandinterpretationofinfectionwouldbefacilitated.Also,alternativemechanismsoftialpreventionandtreatmentshouldbeincludedinini-ofrently.anactivityanti-infectionscreenings.activityDisruptionnotcommonlyofadhesionscreenedisoneexampleforcur-newplant-derivederaAttentionofchemotherapeutictotheseissuesprinciples.

treatmentcouldusherofinfectioninabadlybyneededusingACKNOWLEDGMENT

IgratefullyacknowledgethetechnicalassistanceofEmilyA.Horst.

REFERENCES

1.Abou-Karam,M.,andW.T.Shier.1990.Asimplifiedplaquereductionassayforantiviralagentsfromplants.Demonstrationoffrequentoccur-renceofantiviralactivityinhigherplants.J.Nat.Prod.53:340–344.

578COWAN2.Afolayan,3,5,7-trihydroxyflavoneA.J.,andJ.isolatedJ.M.Meyer.fromthe1997.shootsTheofantimicrobialHelichrysumaureonitensactivityof.J.Ethnopharmacol.57:177–181.

3.Ahmad,A.,J.Davies,S.Randall,andG.R.B.Skinner.1996.AntiviralpropertiesofextractofOpuntiastreptacantha.AntiviralRes.30:75–85.4.Ahmed,A.A.,A.A.Mahmoud,H.J.Williams,A.I.Scott,J.H.Reibenspies,andT.J.Mabry.1993.Newsesquiterpene␣-methylenelactonesfromtheEgyptianplantJasoniacandicans.J.Nat.Prod.56:1276–1280.

5.Akpata,E.S.,andE.O.Akinrimisi.1977.AntibacterialactivityofextractsfromsomeAfricanchewingsticks.OralSurg.OralMed.OralPathol.44:717–722.

6.Ali-Shtayeh,M.S.,M.A.Al-Nuri,R.M.R.Yaghmour,andY.R.Faidi.1997.AntimicrobialactivityofMicromerianervosafromthePalestinian7.area.Alper,J.J.Ethnopharmacol.1998.Effortto58:combat143–147.

microbialresistancelags.ASMNews64:440–441.

8.Amaral,J.A.,A.Ekins,S.R.Richards,andR.Knowles.1998.Effectofselectedmonoterpenesonmethaneoxidation,denitrification,andaerobicmetabolismbybacteriainpureculture.Appl.Environ.Microbiol.64:520–525.

9.Amoros,M.,F.Sauvager,L.Girre,andM.Cormier.1992.Invitroantiviralactivityofpropolis.Apidologie23:231–240.

10.Amoros,M.,C.M.O.Simoes,andL.Girre.1992.Synergisticeffectof

flavonesandflavonolsagainstherpessimplexvirustype1incellculture.Comparisonwiththeantiviralactivityofpropolis.J.Nat.Prod.55:1732–1740.

11.Anonymous.1998.CommissiononDietarySupplementLabelsissuesfinal

report.J.Am.Diet.Assoc.98:270.

12.Anonymous.1997.FANSAreleasesstatementaboutdietarysupplement

labeling.J.Am.Diet.Assoc.97:728–729.

13.Anonymous.1997.FirstINDsubmittedwithFDAforanherbalpharma-ceutical.AIDSWeeklyPlus18.

14.Apisariyakul,A.,N.Vanittanakom,andD.Buddhasukh.1995.Antifungal

activityofturmericoilextractedfromCurcumalonga(Zingiberaceae).J.Ethnopharmacol.49:163–169.

15.Atta-ur-RahmanandM.I.Choudhary.1995.Diterpenoidandsteroidal

alkaloids.Nat.Prod.Rep.12:361–379.

16.Aureli,P.,A.Costantini,andS.Zolea.1992.Antimicrobialactivityofsome

plantessentialoilsagainstListeriamonocytogenes.J.FoodProt.55:344–348.17.Avorn,J.1996.Theeffectofcranberryjuiceonthepresenceofbacteriaand

whitebloodcellsintheurineofelderlywomen.Whatistheroleofbacterialadhesion?Adv.Exp.Med.Biol.408:185–186.

18.Ayafor,J.F.,M.H.K.Tchuendem,andB.Nyasse.1994.Novelbioactive

diterpenoidsfromAframomumaulacocarpos.J.Nat.Prod.57:917–923.19.Balls,A.K.,W.S.Hale,andT.H.Harris.1942.Acrystallineprotein

obtainedfromalipoproteinofwheatflour.CerealChem.19:279–288.20.Balzarini,J.,D.Schols,J.Neyts,E.VanDamme,W.Peumans,andE.De

Clercq.1991.␣-(1,3)-and␣-(1,6)-D-mannose-specificplantlectinsaremarkedlyinhibitorytohumanimmunodeficiencyvirusandcytomegalovirusinfectionsinvitro.Antimicrob.AgentsChemother.35:410–416.

21.Barnard,D.L.,J.H.Huffman,L.R.Meyerson,andR.W.Sidwell.1993.

Modeofinhibitionofrespiratorysyncytialvirusbyaplantflavonoid.Che-motherapy39:212–217.

22.Barre,J.T.,B.F.Bowden,J.C.Coll,J.Jesus,V.E.Fuente,G.C.Janairo,

andC.Y.Ragasa.1997.AbioactivetriterpenefromLantanacamara.Phytochemistry45:321–324.

23.Batista,O.,A.Duarte,J.Nascimento,andM.F.Simones.1994.Structure

andantimicrobialactivityofditerpenesfromtherootsofPlectranthushereroensis.J.Nat.Prod.57:858–861.

24.Berkada,B.1978.Preliminaryreportonwarfarinforthetreatmentof

herpessimplex.J.IrishColl.Phys.Surg.22(Suppl.):56.

25.Borris,R.P.1996.Naturalproductsresearch:perspectivesfromamajor

pharmaceuticalcompany.J.Ethnopharmacol.51:29–38.

26.Bose,P.K.1958.Onsomebiochemicalpropertiesofnaturalcoumarins.

J.IndianChem.Soc.58:367–375.

27.Bosland,P.W.1994.Chiles:history,cultivationanduses,p.347–366.InG.

Charalambous(ed.),Spices,herbsandediblefungi.Elsevier,NewYork,N.Y.

28.Bourinbaiar,A.S.,andS.LeeHuang.1996.Theactivityofplant-derived

antiretroviralproteinsMAP30andGAP31againstherpessimplexvirusinfectioninvitro.Biochem.Biophys.Res.Commun.219:923–929.

29.Brandao,M.G.L.,A.U.Krettli,L.S.R.Soares,C.G.C.Nery,andH.C.

Marinuzzi.1997.AntimalarialactivityofextractsandfractionsfromBidenspilosaandotherBidensspecies(Asteraceae)correlatedwiththepresenceofacetyleneandflavonoidcompounds.J.Ethnopharmacol.57:131–138.30.Brantner,A.,andE.Grein.1994.Antibacterialactivityofplantextracts

usedexternallyintraditionalmedicine.J.Ethnopharmacol.44:35–40.31.Brantner,A.,Z.Males,S.Pepeljnjak,andA.Antolic.1996.Antimicrobial

activityofPaliurusspina-christimill.J.Ethnopharmacol.52:119–122.

32.Brinkworth,R.I.,M.J.Stoermer,andD.P.Fairlie.1992.Flavonesare

inhibitorsofHIV-1proteinase.Biochem.Biophys.Res.Commun.188:631–637.

CLIN.MICROBIOL.REV.

33.Brownlee,fungaleffectsH.E.,ofcocoaA.R.tanninMcEuen,onJ.theHedger,witches’andbroomI.M.pathogenScott.1990.CrinipellisAnti-perniciosa.Physiol.Mol.PlantPathol.36:39–48.

34.Burdick,E.M.1971.Carpaine,analkaloidofCaricapapaya.Itschemistry

andpharmacology.Econ.Bot.25:363–365.

35.Butler,InR.W.L.HemingwayG.1988.EffectsandJ.ofJ.condensedKarchesy(ed.),tanninChemistryonanimalandnutrition,significancep.553.

ofcondensedtannins.PlenumPress,NewYork,N.Y.

36.Cardellina,J.H.I.,M.H.G.Munro,R.W.Fuller,K.P.Manfredi,T.C.

McKee,M.Tischler,H.R.Bokesch,K.R.Gustafson,J.A.Beutler,andM.R.Boyd.1993.AchemicalscreeningstrategyforthedereplicationandprioritizationofHIV-inhibitoryaqueousnaturalproductsextracts.J.Nat.Prod.56:1123–1129.

37.Casley-Smith,J.R.,andJ.R.Casley-Smith.1997.Coumarininthetreat-mentoflymphoedemaandotherhigh-proteinoedemas,p.348.InR.O’KennedyandR.D.Thornes(ed.),Coumarins:biology,applicationsandmodeofaction.JohnWiley&Sons,Inc.,NewYork,N.Y.

38.Chabot,S.,R.Bel-Rhlid,R.Chenevert,andY.Piche.1992.Hyphalgrowth

promotioninvitrooftheVAmycorrhizalfungus,GigasporamargaritaBeckerandHall,bytheactivityofstructurallyspecificflavonoidcompounds39.underChaurasia,CO2-enrichedconditions.NewPhytol.122:461–467.

S.C.,andK.K.Vyas.1977.Invitroeffectofsomevolatileoil

againstPhytophthoraparasiticavar.piperina.J.Res.IndianMed.YogaHomeopath.1977:24–26.

40.Chen,K.,Q.Shi,Y.Kashiwada,D.C.Zhang,C.Q.Hu,J.Q.Jin,H.

Nozaki,R.E.Kilkuskie,E.Tramontano,Y.C.Cheng,etal.1992.Anti-AIDSwilfordiiagents.,andthe6.Salaspermicstructure-activityacid,ancorrelationanti-HIVwithprincipleitsrelatedfromTripterygiumcompounds.J.Nat.Prod.55:340–346.

41.Chessin,M.,D.DeBorde,andA.Zipf(ed.).1995.Antiviralproteinsin

higherplants.CRCPress,Inc.,BocaRaton,Fla.

42.Cichewicz,R.H.,andP.A.Thorpe.1996.Theantimicrobialpropertiesof

chilepeppers(Capsicumspecies)andtheirusesinMayanmedicine.J.Ethnopharmacol.52:61–70.

43.Clark,A.M.1996.Naturalproductsasaresourcefornewdrugs.Pharm.

Res.13:1996.

44.Coe,S.D.1994.America’sfirstcuisines.UniversityofTexasPress,Austin.45.Colilla,F.J.,A.Rocher,andE.Mendez.1990.Gamma-purothionins:amino

acidsequenceoftwopolypeptidesofanewfamilyofthioninsfromwheatendosperm.FEBSLett.270:191–194.

46.Corbeau,P.,M.Haran,H.Binz,andC.Devaux.1994.Jacalin,alectinwith

anti-HIV-1properties,andHIV-1gp120envelopeproteininteractwithdistinctregionsoftheCD4molecule.Mol.Immunol.31:569–575.

47.Cordell,G.A.,andO.E.Araujo.1993.Capsaicin:identification,nomen-clature,andpharmacotherapy.Ann.Pharmacother.27:330–336.

48.Critchfield,J.W.,S.T.Butera,andT.M.Folks.1996.InhibitionofHIV

activationinlatentlyinfectedcellsbyflavonoidcompounds.AIDSRes.Hum.Retroviruses12:39.

49.Croom,E.M.,Jr.,andL.Walker.1995.Botanicalsinthepharmacy:new

lifeforoldremedies.DrugTop.139:84–93.

50.DeBolle,M.F.,R.W.Osborn,I.J.Goderis,L.Noe,D.Acland,C.A.Hart,

S.Torrekens,F.VanLeuven,andN.F.Broekart.1996.AntimicrobialpropertiesfromMirablisjalapaandAmaranthuscaudalus:expression,pro-cessing,localizationandbiologicalactivityintransgenictobacco.PlantMol.Biol.31:993–1008.

51.DeClercq,E.1995.Antiviraltherapyforhumanimmunodeficiencyvirus

infections.Clin.Microbiol.Rev.8:200–239.

52.DeClercq,E.1992.Newperspectivesforthechemotherapyofchemopro-phylaxisofAIDS(acquiredimmunodeficiencysyndrome).Verhandelingen54:57–89.

53.DePasquale,R.,M.P.Germano,A.Keita,R.Sanogo,andL.Iauk.1995.

AntiulceractivityofPteleopsissuberosa.J.Ethnopharmacol.47:55–58.54.Dhuley,J.1998.TherapeuticefficacyofAshwagandhaagainstexperimental

aspergillosisinmice.Immunopharmacol.Immunotoxicol.20:191–198.55.DiStasi,L.C.1995.Amoebicidalcompoundsfrommedicinalplants.Paras-sitologia37:29–39.

56.Dixon,R.A.,P.M.Dey,andC.J.Lamb.1983.Phytoalexins:enzymology

andmolecularbiology.Adv.Enzymol.55:1–69.

57.Dornberger,K.,V.Bockel,J.Heyer,C.Schonfeld,M.Tonew,andE.Tonew.

1975.StudiesontheisothiocyanateserysolinandsulforaphanfromCar-dariadraba.Pharmazie30:792–796.

58.Duke,J.A.1985.Handbookofmedicinalherbs.CRCPress,Inc.,Boca

Raton,Fla.

59.Dwivedi,C.,andA.Abu-Ghazaleh.1997.Chemopreventiveeffectsofsan-dalwoodoilonskinpapillomasinmice.Eur.J.CancerPrev.6:399–401.60.Eisenberg,D.M.,R.C.Kessler,C.Foster,F.E.Norlock,D.R.Calkins,and

T.L.Delbanco.1993.UnconventionalmedicineintheUnitedStates:prev-alence,costsandpatternsofuse.N.Engl.J.Med.328:246–252.

61.Eloff,J.N.1998.Whichextractantshouldbeusedforthescreeningand

isolationofantimicrobialcomponentsfromplants?J.Ethnopharmacol.60:1–8.

62.Estevez-Braun,A.,R.Estevez-Reyes,L.M.Moujir,A.G.Ravelo,andA.G.

VOL.12,1999

Gonzalez.1994.Antibioticactivityandabsoluteconfigurationof8S-hepta-deca-2(Z),9(Z)-diene-4,6-diyne-1,8-diolfromBupleurumsalicifolium.J.Nat.Prod.57:1178–1182.

63.Farley,D.1993.Makingsurehypedoesn’toverwhelmscience.FDACon-sumer27:8–13.

64.

Favero,J.,P.Corbeau,M.Nicolas,M.Benkirane,G.Trave,J.F.P.Dixon,P.Aucouturier,S.Rasheed,andJ.W.Parker.1993.InhibitionofhumanimmunodeficiencyvirusinfectionbythelectinjacalinandbyaderivedpeptideshowingasequencesimilaritywithGP120.Eur.J.Immunol.23:179–185.

65.FernandesdeCaleya,R.,B.Gonzalez-Pascual,F.Garcia-Olmedo,andP.Carbonero.1972.Susceptibilityofphytopathogenicbacteriatowheatpu-rothioninsinvitro.Appl.Microbiol.23:998–1000.

66.Fernandez,activityoftheM.phenolicA.,M.D.acidsGarcia,fractionandofM.ScrophulariaT.Saenz.frutescens1996.AntibacterialandScro-phulariasambucifolia.J.Ethnopharmacol.53:11–14.

67.Fesen,M.R.,K.W.Kohn,F.Leteurtre,andY.Pommier.1993.Inhibitorsofhumanimmunodeficiencyvirusintegrase.Proc.Natl.Acad.Sci.USA90:2399–2403.

68.Fesen,M.R.,Y.Pommier,F.Leteurte,S.Hiroguchi,J.Yung,andK.Kohn.1994.InhibitionofHIV-1integrasebyflavones,caffeicacidphenethylester(CAPE)andrelatedcompounds.Biochem.Pharmacol.48:595–608.

69.Fessenden,R.J.,andJ.S.Fessenden.1982.Organicchemistry,2nded.WillardGrantPress,Boston,Mass.

70.Flayeh,K.A.,andK.D.Sulayman.1987.Antimicrobialactivityoftheaminefractionofcucumber(Cucumissativus)extract.J.Appl.Microbiol.3:275–279.

71.FoodandDrugAdministration.1997.FDAtalkpaper:FDApublishesfinaldietarysupplementrules,publicationT97-45.PressOffice,FoodandDrugAdministration,Washington,D.C.

72.

Francois,G.,L.AkeAssi,J.Holenz,andG.Bringmann.1996.ConstituentsofPicralimanitidadisplaypronouncedinhibitoryactivitiesagainstasexualerythrocyticformsofPlasmodiumfalciparuminvitro.J.Ethnopharmacol.54:113–117.

73.Freiburghaus,F.,R.Kaminsky,M.H.H.Nkunya,andR.Brun.1996.EvaluationofAfricanmedicinalplantsfortheirinvitrotrypanocidalactiv-ity.J.Ethnopharmacol.55:1–11.

74.

Fujioka,T.,andY.Kashiwada.1994.Anti-AIDSagents.11.Betulinicacidandplatanicacidasanti-HIVprinciplesfromSyzigiumclaviflorum,andtheanti-HIVactivityofstructurallyrelatedtriterpenoids.J.Nat.Prod.57:243–247.

75.Gautam,C.S.,P.Pandhi,andP.L.Sharma.1993.Effectoforaladmin-istrationofAbana,anayurvedicformulation,onexperimentalcardiacar-rhythmias.IndianJ.Pharmacol.2:105–106.

76.

Geissman,T.A.1963.Flavonoidcompounds,tannins,ligninsandrelatedcompounds,p.265.InM.FlorkinandE.H.Stotz(ed.),Pyrrolepigments,isoprenoidcompoundsandphenolicplantconstituents,vol.9.Elsevier,NewYork,N.Y.

77.Georges,M.,andK.M.Pandelai.1949.Investigationsonplantantibiotics.IV.FurthersearchforantibioticsubstancesinIndianmedicinalplants.IndianJ.Med.Res.37:169–181.

78.Ghoshal,S.,B.N.KrishnaPrasad,andV.Lakshmi.1996.AntiamoebicactivityofPiperlongumfruitsagainstEntamoebahistolyticainvitroandinvivo.J.Ethnopharmacol.50:167–170.

79.

Giron,L.M.,G.A.Aguilar,A.Caceres,andG.L.Arroyo.1988.Antican-didalactivityofplantsusedforthetreatmentofvaginitisinGuatemalaandclinicaltrialofaSolanumnigrescenspreparation.J.Ethnopharmacol.22:307–313.

80.

Gnabre,J.N.,J.N.Brady,D.J.Clanton,Y.Ito,J.Dittmer,R.B.Bates,andR.C.C.Huang.1995.Inhibitionofhumanimmunodeficiencyvirustype1transcriptionandreplicationbyDNAsequence-selectiveplantlignans.Proc.Natl.Acad.Sci.USA92:11239–11243.

81.

Gollapudi,S.,H.A.Sharma,S.Aggarwal,L.D.Byers,H.E.Ensley,andS.Gupta.1995.Isolationofapreviouslyunidentifiedpolysaccharide(MAR-10)fromHyssopofficinalisthatexhibitsstrongactivityagainsthumanim-munodeficiencyvirustype1.Biochem.Biophys.Res.Commun.210:145–151.

82.Habtemariam,S.,A.I.Gray,andP.G.Waterman.1993.Anewantibac-terialsesquiterpenefromPremnaoligotricha.J.Nat.Prod.56:140–143.83.Hamburger,H.,andK.Hostettmann.1991.Thelinkbetweenphytochem-istryandmedicine.Phytochemistry30:3864–3874.

84.Harrigan,G.G.,A.Ahmad,N.Baj,T.E.Glass,A.A.L.Gunatilaka,andD.G.I.Kingston.1993.BioactiveandothersesquiterpenoidsfromPorellacordeana.J.Nat.Prod.56:921–925.

85.Harris,R.S.1963.VitaminsK,p.192–198.InM.FlorkinandE.Stotz(ed.),Pyrrolepigments,isoprenoidcompoundsandphenolicplantconstituents,vol.9.Elsevier,NewYork,N.Y.

86.

Hasegawa,H.,S.Matsumiya,M.Uchiyama,T.Kurokawa,Y.Inouye,R.Kasai,S.Ishibashi,andK.Yamasaki.1994.Inhibitoryeffectofsometriterpenoidsaponinsonglucosetransportintumorcellsanditsapplicationtoinvitrocytotoxicandantiviralactivities.PlantaMed.6:240–243.

87.

Haslam,E.1996.Naturalpolyphenols(vegetabletannins)asdrugs:possible

ANTIMICROBIALPLANTCHEMICALS579

88.modesHayashi,ofK.,action.M.J.Kamiya,Nat.Prod.and59:T.205–215.

Hayashi.1995.Virucidaleffectsofthe

steamdistillatefromHouttuyniacordataanditscomponentsonHSV-1,influenzavirusandHIV.PlantaMed.61:237–241.

89.Hess,S.C.,R.L.Brum,N.K.Honda,A.B.Cruz,E.Moretto,R.B.Cruz,

I.Messana,F.Ferrari,V.C.Filho,andR.A.Yunes.1995.AntibacterialactivityandphytochemicalanalysisofVochysiadivergens(Vochysiaceae).J.Ethnopharmacol.47:97–100.

90.Himejima,M.,K.R.Hobson,T.Otsuka,D.L.Wood,andI.Kubo.1992.

Antimicrobialderosa:adefenseterpenesmechanismfromoleoresinagainstmicrobialofponderosainvasion.pinetreeJ.Chem.PinusEcol.pon-18:1809–1818.

91.Himejima,M.,andI.Kubo.1991.Antibacterialagentsfromthecashew

Anacardiumoccidentale.J.Agric.FoodChem.39:418–421.

92.Holmes,O.W.1861.Currentsandcounter-currentsinmedicalscience,with

otheraddressesandessays.Ticknor&Fields,Boston,Mass.

93.Hopp,K.H.,L.V.Cunningham,M.C.Bromel,L.J.Schermeister,and

S.K.WahbaKhalil.1976.InvitroantitrypanosomalactivityofcertainalkaloidsagainstTrypanosomalewisi.Lloydia39:375–377.

94.Houghton,P.J.,T.Z.Woldemariam,A.I.Khan,A.Burke,andN.Mah-mood.1994.Antiviralactivityofnaturalandsemi-syntheticchromosomealkaloids.AntiviralRes.25:235–244.

95.Hoult,J.R.S.,andM.Paya.1996.Pharmacologicalandbiochemical

actionsofsimplecoumarins:naturalproductswiththerapeuticpotential.Gen.Pharmacol.27:713–722.

96.Hu,C.Q.,K.Chen,Q.Shi,R.E.Kilkuskie,Y.C.Cheng,andK.H.Lee.

1994.Anti-AIDSprincipleagents.fromChrysanthemum10.Acacetin-7-Omorifolium-beta-D-galactopyranoside,andanti-HIVandastructure-activ-itycorrelationwithsomerelatedflavonoids.J.Nat.Prod.57:42–51.

97.Huang,P.L.,H.C.Chen,H.F.Kung,P.L.Huang,H.I.Huang,andS.

Lee-Huang.1992.Anti-HIVplantproteinscatalyzetopologicalchangesofDNAintoinactiveforms.Biofactors4:37–41.

98.Hudson,J.B.,F.Balza,L.Harris,andG.H.N.Towers.1993.Light-mediatedactivitiesofthiarubrinesagainsthumanimmunodeficiencyvirus.Photochem.Photobiol.57:675–680.

99.Hudson,J.B.,E.A.Graham,L.Harris,andM.J.Ashwood-Smith.1993.

TheunusualUVA-dependentantiviralpropertiesofthefuroisocoumarin,coriandrin.Photochem.Photobiol.57:491–496.

100.Hufford,C.D.,Y.Jia,E.M.Croom,Jr.,I.Muhammed,A.L.Okunade,

A.M.Clark,andR.D.Rogers.1993.AntimicrobialcompoundsfromPetalostemumpurpureum.J.Nat.Prod.56:1878–1889.

101.Hunter,M.D.,andL.A.Hull.1993.Variationinconcentrationsofphlo-ridzinandphloretininapplefoliage.Phytochemistry34:1251–1254.

102.Ito,M.,H.Nakashima,M.Baba,R.Pauwels,E.DeClercq,S.Shigeta,and

N.Yamamoto.1987.Inhibitoryeffectofglycyrrhizinontheinvitroinfec-tivityandcytopathicactivityofthehumanimmunodeficiencyvirus[HIV(HTLV-III/LAV)].Antivir.Res.7:127–137.

103.Ivanovska,N.,S.Philipov,R.Istatkova,andP.Georgieva.1996.Antimi-crobialandimmunologicalactivityofethanolextractsandfractionsfromIsopyrumthalictroides.J.Ethnopharmacol.54:143–151.

104.Iwu,M.M.,N.C.Unaeze,C.O.Okunji,D.G.Corley,D.R.Sanson,and

M.S.Tempesta.1991.AntibacterialaromaticisothiocyanatesfromtheessentialoilofHippocrateawelwitschiiroots.Int.J.Pharmacogn.29:154–158.

105.Jones,G.A.,T.A.McAllister,A.D.Muir,andK.J.Cheng.1994.Effectsof

sainfoin(Onobrychisviciifoliascop.)condensedtanninsongrowthandproteolysisbyfourstrainsofruminalbacteria.Appl.Environ.Microbiol.60:1374–1378.

106.Jones,N.L.,S.Shabib,andP.M.Sherman.1997.Capsaicinasaninhibitor

ofthegrowthofthegastricpathogenHelicobacterpylori.FEMSMicrobiol.Lett.146:223–227.

107.Jones,S.B.,Jr.,andA.E.Luchsinger.1986.Plantsystematics.McGraw-HillBookCo.,NewYork,N.Y.

108.Kadota,S.,P.Basnet,E.Ishii,T.Tamura,andT.Namba.1997.Antibac-terialactivityoftrichorabdalfromRabdosiatrichocarpaagainstHelicobacterpylori.Zentbl.Bakteriol.286:63–67.

109.Kahane,I.,andI.Ofek.1996.Towardanti-adhesiontherapyformicrobial

diseases.PlenumPress,NewYork,N.Y.

110.Kakiuchi,N.,M.Hattori,andT.Namba.1985.Inhibitoryeffectoftannins

onreversetranscriptasefromRNAtumorvirus.J.Nat.Prod.48:614–621.111.Kaul,T.N.,E.Middletown,Jr.,andP.L.Ogra.1985.Antiviraleffectof

flavonoidsonhumanviruses.J.Med.Virol.15:71–79.

112.Kazmi,M.H.,A.Malik,S.Hameed,N.Akhtar,andS.NoorAli.1994.An

anthraquinonederivativefromCassiaitalica.Phytochemistry36:761–763.113.Keating,G.J.,andR.O’Kennedy.1997.Thechemistryandoccurrenceof

coumarins,p.348.InR.O’KennedyandR.D.Thornes(ed.),Coumarins:biology,applicationsandmodeofaction.JohnWiley&Sons,Inc.,NewYork,N.Y.

114.King,S.R.,andM.S.Tempesta.1994.Fromshamantohumanclinical

trials:theroleofindustryinethnobotany,conservationandcommunityreciprocity.CibaFound.Symp.185:197–206.

115.Kitagawa,I.,T.Mahmud,K.-I.Yokota,S.Nakagawa,T.Mayumi,M.

580COWAN

Kobayashi,andH.Shibuya.1996.Indonesianmedicinalplants.XVII.CharacterizationofquassinoidsfromthestemsofQuassiaindica.Chem.Pharm.Bull.44:2009–2014.

116.Klink,B.1997.Alternativemedicines:isnaturalreallybetter?DrugTop.141:99–100.

117.

Klopoukh,MycobacteriumL.,S.chelonaeSiddiqi,andM.Warns,MycobacteriumandL.To.marinum1997.Growthbyplantinhibitioncompounds,ofabstr.A-199.InAbstractsofthe97thGeneralMeetingoftheAmericanSocietyforMicrobiology1997.AmericanSocietyforMicrobiology,Wash-ington,D.C.

118.

Kragh,K.M.,J.E.Nielsen,K.K.Nielsen,S.Dreboldt,andJ.D.Mikkelsen.1995.Characterizationandlocalizationofnewantifungalcys-teine-richproteinsfromBetavulgaris.Mol.Plant-MicrobeInteract.8:424–119.434.

Kreis,W.,M.H.Kaplan,J.Freeman,D.K.Sun,andP.S.Sarin.1990.InhibitionofHIVreplicationbyHyssopofficinalisextracts.AntiviralRes.14:323–337.

120.Kubo,A.,C.S.Lunde,andI.Kubo.1995.Antimicrobialactivityoftheoliveoilflavorcompounds.J.Agric.FoodChem.43:1629–1633.

121.Kubo,I.,H.Muroi,andM.Himejima.1992.Antibacterialactivityoftotarolanditspotentiation.J.Nat.Prod.55:1436–1440.

122.Kubo,I.,H.Muroi,andM.Himejima.1993.Combinationeffectsofanti-fungalnagilactonesagainstCandidaalbicansandtwootherfungiwithphenylpropanoids.J.Nat.Prod.56:220–226.

123.Kubo,I.,H.Muroi,andA.Kubo.1994.Naturallyoccurringanti-acneagents.J.Nat.Prod.57:9–17.

124.Kuhnau,J.1976.Theflavonoids.Aclassofsemi-essentialfoodcompo-nents:theirroleinhumannutrition.WorldRev.Nutr.Diet.24:117–191.125.Kumar,O.,andB.Singh.1992.Effectofayurvedicliverstimulantsonliveweightgainofbroilersinnortheasternregion.IndianJ.Anim.Res.26:1–5.126.Lai,P.K.,J.Donovan,H.Takayama,H.Sakagami,A.Tanaka,K.Konno,andM.Nonoyama.1990.Modificationofhumanimmunodeficiencyviralreplicationbypineconeextracts.AIDSRes.Hum.Retroviruses6:205–217.127.Lee,C.D.,M.Ott,S.P.Thyagarajan,D.A.Shafritz,R.D.Burk,andS.Gupta.1996.PhyllanthusamarusdownregulateshepatitisBvirusmRNAtranscriptionandreplication.Eur.J.Clin.Investig.26:1069–1076.

128.Lee-Huang,S.,P.L.Huang,H.C.Chen,P.L.Huang,A.Bourinbaiar,H.I.Huang,andH.F.Kung.1995.Anti-HIVandanti-tumoractivitiesofre-combinantMAP30frombittermelon.Gene(Amsterdam)161:151–156.129.

Lee-Huang,S.,P.L.Huang,P.L.Huang,A.S.Bourinbaiar,H.C.Chen,andH.F.Kung.1995.Inhibitionoftheintegraseofhumanimmunodefi-ciencyvirus(HIV)type1byanti-HIVplantproteinsMAP30andGAP31.Proc.Natl.Acad.Sci.USA92:8818–8822.

130.

Lee-Huang,S.,H.F.Kung,P.L.Huang,A.S.Bourinbaiar,J.L.Morell,J.H.Brown,P.L.Huang,W.P.Tsai,A.Y.Chen,H.I.Huang,andH.C.Chen.1994.Humanimmunodeficiencyvirustype1(HIV-1)inhibition,DNA-binding,RNA-bindingandribosomeinactivationactivitiesintheN-terminalsegmentsoftheplantanti-HIVprotein.Proc.Natl.Acad.Sci.USA91:12208–12212.

131.Lewis,W.H.,andM.P.Elvin-Lewis.1995.Medicinalplantsassourcesofnewtherapeutics.Ann.Mo.Bot.Gard.82:16–24.

132.Liener,I.E.1970.Toxicconstituentsofplantfoodstuffs.Proc.Nutr.Soc.29:56–57.

133.

Manonmani,S.,V.P.Vishwanathan,S.Subramanian,andS.Govin-dasamy.1995.BiochemicalstudiesontheantiulcerogenicactivityofCau-very100,anayurvedicformulationinexperimentalulcers.IndianJ.Phar-macol.27:101–105.

134.Manonmani,S.,S.William,S.Subramanian,andS.Govindasamy.1991.BiochemicalstudiesontheantidiarrhoealeffectsofCauvery-100,anayurvedicformulation,inrats.Biochem.Int.24:701–708.

135.Martin,G.J.1995.Ethnobotany:amethodsmanual.Chapman&Hall,NewYork,N.Y.

136.Martinez,M.J.,J.Betancourt,N.Alonso-Gonzalez,andA.Jauregui.1996.ScreeningofsomeCubanmedicinalplantsforantimicrobialactivity.J.Ethnopharmacol.52:171–174.

137.Mason,T.L.,andB.P.Wasserman.1987.Inactivationofredbeetbeta-glucansynthasebynativeandoxidizedphenoliccompounds.Phytochem-istry26:2197–2202.

138.Mayr-Harting,A.,A.Hedges,andR.Berkelery(ed.).1972.Methodsforstudyingbacteriocins.AcademicPress,Inc.,NewYork,N.Y.

139.Mazumder,A.,D.Cooney,R.Agbaria,andY.Pommier.1994.Inhibitionofhumanimmunodeficiencyvirustype1integraseby3Ј-azido-3Ј-deoxythymi-dylate.Proc.Natl.Acad.Sci.USA91:5771–5775.

140.

McDevitt,J.T.,D.M.Schneider,S.K.Katiyar,andT.D.Edlind.1996.Berberine:acandidateforthetreatmentofdiarrheainAIDSpatients,abstr.175.InProgramandAbstractsofthe36thInterscienceConferenceonAntimicrobialAgentsandChemotherapy.AmericanSocietyforMicro-biology,Washington,D.C.

141.

McGrath,M.S.,K.M.Hwang,S.E.Caldwell,I.Gaston,K.C.Luk,P.Wu,V.L.Ng,S.Crowe,J.Daniels,J.Marsh,etal.1989.GLQ223:aninhibitorofhumanimmunodeficiencyvirusreplicationinacutelyandchronicallyinfectedcellsoflymphocyteandmononuclearphagocytelineage.Proc.

CLIN.MICROBIOL.REV.

142.Natl.McMahon,Acad.J.Sci.B.,USAM.J.86:Currens,2844–2848.

R.J.Gulakowski,R.W.J.Buckheit,C.

Lackman-Smith,Y.F.Hallock,andM.R.Boyd.1995.MichellamineB,anovelplantalkaloid,inhibitshumanimmunodeficiencyvirus-inducedcellkillingbyatleasttwodistinctmechanisms.Antimicrob.AgentsChemother.39:484–488.

143.Mendez,E.,A.Moreno,F.Colilla,F.Pelaez,G.G.Limas,R.Mendez,F.

Soriano,M.Salinas,andC.DeHaro.1990.Primarystructureandinhibi-tionofproteinsynthesisineukaryoticcell-freesystemofanovelthionin,gamma-horothionin,frombarleyendosperm.Eur.J.Biochem.194:533–539.

144.Mendoza,L.,M.Wilkens,andA.Urzua.1997.Antimicrobialstudyofthe

resinousexudatesandofditerpenoidsandflavonoidsisolatedfromsomeChileanPseudognaphalium(Asteraceae).J.Ethnopharmacol.58:85–88.145.Meyer,J.J.M.,A.J.Afolayan,M.B.Taylor,andD.Erasmus.1997.

AntiviralactivityofgalanginfromtheaerialpartsofHelichrysumaureo-nitens.J.Ethnopharmacol.56:165–169.

146.Moerman,D.E.1996.Ananalysisofthefoodplantsanddrugplantsof

nativeNorthAmerica.J.Ethnopharmacol.52:1–22.

147.Moore,P.S.,andC.Pizza.1992.ObservationsontheinhibitionofHIV-1

reversetranscriptasebycatechins.Biochem.J.288:717–719.

148.Muller,W.E.G.,K.Renneisen,M.H.Kreuter,H.C.Schroder,andI.

Winkler.1988.TheD-mannose-specificlectinfromGerardiasavagliablocksbindingofhumanimmunodeficiencyvirustypeItoH9cellsandhumanlymphocytesinvitro.J.AcquiredImmuneDefic.Syndr.1:453–458.

149.Murakami,A.,H.Ohigashi,S.Tanaka,A.Tatematsu,andK.Koshimizu.

1993.BittercyanoglucosidesfromLophiraalata.Phytochemistry32:1461–1466.

150.Naganawa,R.,N.Iwata,K.Ishikawa,H.Fukuda,T.Fujino,andA.Suzuki.

1996.Inhibitionofmicrobialgrowthbyajoene,asulfur-containingcom-poundderivedfromgarlic.Appl.Environ.Microbiol.62:4238–4242.

151.Nakahara,K.,S.Kawabata,H.Ono,K.Ogura,T.Tanaka,T.Ooshima,

andS.Hamada.1993.Inhibitoryeffectofoolongteapolyphenolsonglu-cosyltransferasesofmutansstreptococci.Appl.Environ.Microbiol.59:968–973.

152.Namba,T.,O.Morita,S.-L.Huang,K.Goshima,M.Hattori,andN.

Kakiuchi.1988.Studiesoncardio-activecrudedrugs.I.Effectofcoumarinsonculturedmyocardialcells.PlantaMed.54:277–282.

153.Navarro,V.,M.L.Villarreal,G.Rojas,andX.Lozoya.1996.Antimicrobial

evaluationofsomeplantsusedinMexicantraditionalmedicineforthetreatmentofinfectiousdiseases.J.Ethnopharmacol.53:143–147.

154.Ngan,F.,R.S.Chang,H.D.Tabba,andK.M.Smith.1988.Isolation,

purificationandpartialcharacterizationofanactiveanti-HIVcompoundfromtheChinesemedicinalherbViolayedoensis.AntiviralRes.10:107–116.155.Nonaka,G.-I.,I.Nishioka,M.Nishizawa,T.Yamagishi,Y.Kashiwada,

G.E.Dutschman,A.J.Bodner,R.E.Kilkuskie,Y.-C.Cheng,andK.-H.Lee.1990.Anti-AIDSagents.2.InhibitoryeffectsoftanninsonHIVreversetranscriptaseandHIVreplicationinH9lymphocytecells.J.Nat.Prod.53:587–595.

156.Norton,M.R.,andM.Addy.1989.Chewingsticksversustoothbrushesin

WestAfrica.Apilotstudy.Clin.Prev.Dent.113:11–13.

157.Odebiyi,O.O.,andE.A.Sofowora.1979.Antimicrobialalkaloidsfroma

Nigerianchewingstick(Fagarazanthoxyloides).PlantaMed.36:204–207.158.Ofek,I.,J.Goldhar,andN.Sharon.1996.Anti-Escherichiacoliadhesin

activityofcranberryandblueberryjuices.Adv.Exp.Med.Biol.408:179–183.

159.Ofek,I.,J.Goldhar,D.Zafriri,H.Lis,R.Adar,andN.Sharon.1991.

Anti-Escherichiacoliadhesinactivityofcranberryandblueberryjuices.N.Engl.J.Med.324:1599.(Letter.)

160.Offergeld,R.,C.Reinecker,E.Gumz,S.Schrum,R.Treiber,R.D.Neth,

andS.H.Gohla.1992.MitogenicactivityofhighmolecularpolysaccharidefractionsisolatedfromthecuppressaceaeThujaoccidentalisL.enhancedcytokine-productionbythyapolysaccharide,g-fraction(TPSg).Leukemia6(Suppl.3):189S–191S.

161.O’Kennedy,R.,andR.D.Thornes(ed.).1997.Coumarins:biology,appli-cationsandmodeofaction.JohnWiley&Sons,Inc.,NewYork,N.Y.162.Oliver-Bever,B.1986.MedicinalplantsintropicalWestAfrica.Cambridge

UniversityPress,NewYork,N.Y.

163.Omulokoli,E.,B.Khan,andS.C.Chhabra.1997.Antiplasmodialactivity

offourKenyanmedicinalplants.J.Ethnopharmacol.56:133–137.

164.Ono,K.,H.Nakane,M.Fukishima,J.-C.Chermann,andF.Barre-Sin-oussi.1989.Inhibitionofreversetranscriptaseactivitybyaflavonoidcom-pound,5,6,7-trihydroxyflavone.Biochem.Biophys.Res.Commun.3:982–987.

165.Ono,K.,H.Nakane,M.Fukushima,J.-C.Chermann,andF.Barre-Sin-oussi.1990.DifferentialinhibitoryeffectsofvariousflavonoidsontheactivitiesofreversetranscriptaseandcellularDNAandRNApolymerases.Eur.J.Biochem.190:469–476.

166.Ooshima,T.,T.Minami,W.Aono,A.Izumitani,S.Sobue,T.Fujiwara,S.

Kawabata,andS.Hamada.1993.Oolongteapolyphenolsinhibitexperi-mentaldentalcariesinSPFratsinfectedwithmutansstreptococci.CariesRes.27:124–129.

VOL.12,1999

167.Orozco-Topete,R.,J.Sierra-Madero,C.Cano-Dominguez,J.Kersheno-vich,G.Ortiz-Pedroza,E.Vazquez-Valls,C.Garcia-Cosio,A.Soria-Cor-doba,A.M.Armendariz,X.Teran-Toledo,J.Romo-Garcia,H.Fernandez,andE.J.Rozhon.1997.SafetyandefficacyofVirendfortopicaltreatmentofgenitalandanalherpessimplexlesionsinpatientswithAIDS.AntiviralRes.35:91–103.

168.Osato,J.A.,L.A.Santiago,G.M.Remo,M.S.Cuadra,andA.Mori.1993.

Antimicrobialandantioxidantactivitiesofunripepapaya.LifeSci.53:1383–1389.

169.Pantazis,P.1996.Camptothecin:apromisingantiretroviraldrug.

J.Biomed.Sci.3:14–19.

170.Paranjpe,P.,andP.H.Kulkarni.1995.Comparativeefficacyoffour

Ayuredicformulationsinthetreatmentofacnevulgaris:adouble-blindrandomisedplacebo-controlledclinicalevaluation.J.Ethnopharmacol.49:127–132.

171.Paris,A.,B.Strukelj,M.Renko,andV.Turk.1993.Inhibitoryeffectof

carnosolicacidonHIV-1proteaseincell-freeassays.J.Nat.Prod.56:1426–1430.

172.Pengsuparp,T.,L.Cai,H.Constant,H.H.Fong,L.Z.Lin,A.D.Kinghorn,

J.M.Pezzuto,G.A.Cordell,K.Ingolfsdottir,andH.Wagner.1995.Mech-anisticevaluationofnewplant-derivedcompoundsthatinhibitHIV-1re-versetranscriptase.J.Nat.Prod.58:1024–1031.

173.Pengsuparp,T.,L.Cai,H.H.S.Fong,A.D.Kinghorn,J.M.Pezzuto,M.C.

Wani,andM.E.Wall.1994.PentacyclictriterpenesderivedfromMaprou-neaafricanaarepotentinhibitorsofHIV-1reversetranscriptase.J.Nat.Prod.57:415–418.

174.Peres,M.T.L.P.,F.D.Monache,A.B.Cruz,M.G.Pizzolatti,andR.A.

Yunes.1997.ChemicalcompositionandantimicrobialactivityofCrotonurucuranaBaillon(Euphorbiaceae).J.Ethnopharmacol.56:223–226.

175.Perrett,S.,P.J.Whitfield,L.Sanderson,andA.Bartlett.1995.Theplant

molluscicideMillettiathonningii(Leguminosae)asatopicalantischistoso-malagent.J.Ethnopharmacol.47:49–54.

176.Phillipson,J.D.,andM.J.O’Neill.1987.Newleadstothetreatmentof

protozoalinfectionsbasedonnaturalproductmolecules.ActaPharm.Nord.1:131–144.

177.Piller,N.B.1975.Acomparisonoftheeffectivenessofsomeanti-inflam-matorydrugsonthermaloedema.Br.J.Exp.Pathol.56:554–559.

178.Prpic-Majic,D.,A.Pizent,J.Jurasovic,J.Pongracic,andN.Restek-Samarzija.1996.LeadpoisoningassociatedwiththeuseofAyurvedicmetal-mineraltonics.J.Toxicol.Clin.Toxicol.34:417–423.

179.Rana,B.K.,U.P.Singh,andV.Taneja.1997.Antifungalactivityand

kineticsofinhibitionbyessentialoilisolatedfromleavesofAeglemarmelos.J.Ethnopharmacol.57:29–34.

180.Rao,K.V.,K.Sreeramulu,D.Gunasekar,andD.Ramesh.1993.Twonew

sesquiterpenelactonesfromCeibapentandra.J.Nat.Prod.56:2041–2045.181.Rinehart,K.L.,T.G.Holt,N.L.Fregeau,P.A.Keifer,G.R.Wilson,T.J.

Perun,Jr.,R.Sakai,A.G.Thompson,J.G.Stroh,L.S.Shield,andD.S.Seigler.1990.Bioactivecompoundsfromaquaticandterrestrialsources.J.Nat.Prod.53:771–792.

182.Rojas,A.,L.Hernandez,R.Pereda-Miranda,andR.Mata.1992.Screening

forantimicrobialactivityofcrudedrugextractsandpurenaturalproductsfromMexicanmedicinalplants.J.Ethnopharmacol.35:275–283.

183.Rotimi,V.O.,B.E.Laughon,J.G.Bartlett,andH.A.Mosadami.1988.

ActivitiesofNigerianchewingstickextractsagainstBacteroidesgingivalisandBacteroidesmelaninogenicus.Antimicrob.AgentsChemother.32:598–600.

184.Rucker,G.,S.Kehrbaum,H.Sakulas,B.Lawong,andF.Goeltenboth.

1992.AcetylenicglucosidesfromMicroglossapyrifolia.PlantaMed.58:266–269.

185.Sakanaka,S.,M.Kim,M.Taniguchi,andT.Yamamoto.1989.Antibacte-rialsubstancesinJapanesegreenteaextractagainstStreptococcusmutans,acariogenicbacterium.Agric.Biol.Chem.53:2307–2311.

186.Sakanaka,S.,N.Shimura,M.Aizawa,M.Kim,andT.Yamamoto.1992.

Preventiveeffectofgreenteapolyphenolsagainstdentalcariesinconven-tionalrats.Biosci.Biotechnol.Biochem.56:592–594.

187.San-Blas,G.,L.Marino,F.San-Blas,andR.Apitz-Castro.1993.Effectof

ajoeneondimorphismofParacoccidioidesbrasiliensis.J.Med.Vet.Mycol.31:133–141.

188.San-Blas,G.,F.San-Blas,F.Gil,L.Marino,andR.Apitz-Castro.1989.

InhibitionofgrowthofthedimorphicfungusParacoccidioidesbrasiliensisbyajoene.Antimicrob.AgentsChemother.33:1641–1644.

189.Sato,M.,S.Fujiwara,H.Tsuchiya,T.Fujii,M.Iinuma,H.Tosa,andY.

Ohkawa.1996.Flavoneswithantibacterialactivityagainstcariogenicbac-teria.J.Ethnopharmacol.54:171–176.

190.Sato,Y.,H.Odetani,K.Singyouchi,T.Ohtsubo,M.Kihara,H.Shibata,

andT.Higuti.1997.ExtractionandpurificationofeffectiveantimicrobialconstituentsofTerminaliachebulaRETSagainstmethicillin-resistantStaphylococcusaureus.Biol.Pharm.Bull.20:401–404.

191.Satrija,F.,P.Nansen,S.Murtini,andS.He.1995.Anthelminticactivityof

papayalatexagainstpatentHeligmosomoidespolygyrusinfectionsinmice.J.Ethnopharmacol.48:161–164.

ANTIMICROBIALPLANTCHEMICALS581

192.Scalbert,A.1991.Antimicrobialpropertiesoftannins.Phytochemistry30:

3875–3883.

193.Scheel,L.D.1972.Thebiologicalactionofthecoumarins.Microbiol.

Toxins8:47–66.

194.Schmidt,H.1988.Phenoloxidase(E.I.14.18.1),amarkerenzymeforde-fensecells.Progressinhistochemistryandcytochemistry,vol.17.GustavFischer,NewYork,N.Y.

195.Schultes,R.E.1978.Thekingdomofplants,p.208.InW.A.R.Thomson

(ed.),MedicinesfromtheEarth.McGraw-HillBookCo.,NewYork,N.Y.196.Schultz,J.C.1988.Tannin-insectinteractions,p.553.InR.W.Hemingway

andJ.J.Karchesy(ed.),Chemistryandsignificanceofcondensedtannins.PlenumPress,NewYork,N.Y.

197.Scortichini,M.,andM.PiaRossi.1991.Preliminaryinvitroevaluationof

theantimicrobialactivityofterpenesandterpenoidstowardsErwiniaamy-lovora(Burrill)Winslowetal.J.Appl.Bacteriol.71:109–112.

198.Serafini,M.,A.Ghiselli,andA.Ferro-Luzzi.1994.Redwine,teaand

anti-oxidants.Lancet344:626.

199.Serkedjieva,J.,andN.Manolova.1992.Anti-influenzaviruseffectofsome

propolisconstituentsandtheiranalogues(estersofsubstitutedcinnamicacids).J.Nat.Prod.55:294–297.

200.Sethi,M.L.1979.Inhibitionofreversetranscriptaseactivitybybenzo-phenanthridinealkaloids.J.Nat.Prod.42:187–196.

201.Shah,L.,S.P.Patil,andJ.Patil.1997.Observationsonclinicalevaluation

ofindigenousherbaldrugsinthetreatmentofmentalillnesses.IndianJ.Pharmacol.29:S347–S349.

202.Sharon,N.,andI.Ofek.1986.Mannosespecificbacterialsurfacelectins,p.

55–82.InD.Mirelman(ed.),Microbiallectinsandagglutinins.JohnWiley&Sons,Inc.,NewYork,N.Y.

203.Silva,O.,A.Duarte,J.Cabrita,M.Pimentel,A.Diniz,andE.Gomes.1996.

AntimicrobialactivityofGuinea-Bissautraditionalremedies.J.Ethno-pharmacol.50:55–59.

204.Silva,O.,A.Duarte,M.Pimental,S.Viegas,H.Barroso,J.Machado,I.

Pires,J.Cabrita,andE.Gomes.1997.AntimicrobialactivityofTerminaliamacropteraroot.J.Ethnopharmacol.57:203–207.

205.Sohni,Y.R.,P.Kaimal,andR.M.Bhatt.1995.Theantiamoebiceffectof

acrudedrugformationofherbalextractsagainstEntamoebahistolyticainvitroandinvivo.J.Ethnopharmacol.45:43–52.

206.Soine,T.O.1964.Naturallyoccurringcoumarinsandrelatedphysiological

activities.J.Pharm.Sci.53:231–264.

207.Song,Z.J.,H.K.Johansen,V.Faber,andN.Hoiby.1997.Ginsengtreat-mentenhancesbacterialclearanceanddecreaseslungpathologyinathymicratswithchronicPseudomonasaeruginosapneumonia.APMIS105:438–444.

208.Spedding,G.,A.Ratty,andE.J.Middleton.1989.Inhibitionofreverse

transcriptasesbyflavonoids.AntiviralRes.12:99–110.

209.Stange,R.R.,Jr.,S.L.Midland,J.W.Eckert,andJ.J.Sims.1993.An

antifungalcompoundproducedbygrapefruitandValenciaorangeafterwoundingofthepeel.J.Nat.Prod.56:1627–1629.

210.Stern,J.L.,A.E.Hagerman,P.D.Steinberg,andP.K.Mason.1996.

Phlorotannin-proteininteractions.J.Chem.Ecol.22:1887–1899.

211.Stockwell,C.1988.Nature’spharmacy.CenturyHutchinsonLtd.,London,

UnitedKingdom.

212.Sun,H.D.,S.X.Qiu,L.Z.Lin,Z.Y.Wang,Z.W.Lin,T.Pengsuparp,J.M.

Pezzuto,H.H.Fong,G.A.Cordell,andN.R.Farnsworth.1996.Nigranoicacid,atriterpenoidfromSchisandrasphaerandrathatinhibitsHIV-1re-versetranscriptase.J.Nat.Prod.59:525–527.

213.Suresh,B.,S.Sriram,S.A.Dhanaraj,K.Elango,andK.Chinnaswamy.

1997.AnticandidalactivityofSantolinachamaecyparissusvolatileoil.J.Ethnopharmacol.55:151–159.

214.Tabba,H.D.,R.S.Chang,andK.M.Smith.1989.Isolation,purification,

andpartialcharacterizationofprunellin,ananti-HIVcomponentfromaqueousextractsofPrunellavulgaris.AntiviralRes.11:263–273.

215.Tada,M.,Y.Hiroe,S.Kiyohara,andS.Suzuki.1988.Nematicidaland

antimicrobialconstituentsfromAlliumgrayiRegelandAlliumfistulosumL.var.caespitosum.Agric.Biol.Chem.52:2383–2385.

216.Tan,G.T.,J.F.Miller,A.D.Kinghorn,S.H.Hughes,andJ.M.Pezzuto.

1992.HIV-1andHIV-2reversetranscriptases:acomparativestudyofsensitivitytoinhibitionbyselectednaturalproducts.Biochem.Biophys.Res.Commun.185:370–378.

217.Tan,G.T.,J.M.Pezzuto,andA.D.Kinghorn.1991.Evaluationofnatural

productsasinhibitorsofhumanimmunodeficiencyvirustype1(HIV-1)reversetranscriptase.J.Nat.Prod.54:143–154.

218.Tang,glucopyranoside,R.,K.Chen,anM.anti-HIVCosentino,principleandK.-H.fromLee.Kummerowia1994.Apigenin-7-striata.Bioorg.O-␤-D-Med.Chem.Lett.4:455–458.

219.Taniguchi,M.,andI.Kubo.1993.Ethnobotanicaldrugdiscoverybasedon

medicinemen’strialsintheAfricansavanna:screeningofeastAfricanplantsforantimicrobialactivityII.J.Nat.Prod.56:1539–1546.

220.Tassou,C.C.,E.H.Drosinos,andG.J.E.Nychas.1995.Effectsofessential

oilcytogenesfrommintinmodel(Menthafoodpiperitasystems)onatSalmonella4°and10°C.enteritidisJ.Appl.andBacteriol.Listeria78:mono-593–600.

582COWAN221.Taylor,AntimicrobialR.S.L.,F.Edel,N.P.Manandhar,andG.H.pharmacol.50:activities97–102.

ofsouthernNepalesemedicinalN.plants.Towers.J.Ethno-1996.

222.Terras,F.R.G.,H.M.E.Schoofs,H.M.E.Thevissen,R.W.Osborn,J.

Vanderleyden,B.P.A.Cammue,andW.F.Broekaert.1993.Synergisticenhancementoftheantifungalactivityofwheatandbarleythioninsbyradishandoilseedrape2Salbuminsandbybarleytrypsininhibitors.PlantPhysiol.103:1311–1319.

223.Thastrup,O.,J.B.Knudsen,J.Lemmich,andK.Winther.1985.Inhibi-tionsofhumanplateletaggregationbydihydropyrano-anddihydrofurano-coumarins,anewclassofcAMPphosphodiesteraseinhibitors.Biochem.224.Pharmacol.Thomson,W.34:A.2137–2140.

R.(ed.).1978.MedicinesfromtheEarth.McGraw-Hill

BookCo.,Maidenhead,UnitedKingdom.

225.Thornes,coumarins,R.p.D.256.1997.InR.ClinicalO’KennedyandbiologicalandR.D.observationsThornes(ed.),associatedCoumarins:with

biology,applicationsandmodeofaction.JohnWiley&Sons,Inc.,NewYork,N.Y.

226.Toda,M.,S.Okubo,H.Ikigai,T.Suzuki,Y.Suzuki,Y.Hara,andT.

Shimamura.1992.Theprotectiveactivityofteacatechinsagainstexperi-227.mentalToda,M.,infectionS.Okubo,byVibrioR.Ohnishi,choleraeandO1.T.Microbiol.Shimamura.Immunol.1989.Antibacterial

36:999–1001.andbactericidalactivitiesofJapanesegreentea.Jpn.J.Bacteriol.45:561–566.

228.Tsuchiya,H.,M.Sato,M.Iinuma,J.Yokoyama,M.Ohyama,T.Tanaka,I.

Takase,andI.Namikawa.1994.Inhibitionofthegrowthofcariogenicbacteriainvitrobyplantflavanones.Experientia50:846–849.

229.Tsuchiya,H.,M.Sato,T.Miyazaki,S.Fujiwara,S.Tanigaki,M.Ohyama,

T.Tanaka,andM.Iinuma.1996.Comparativestudyontheantibacterialactivitycoccusaureusofphytochemical.J.Ethnopharmacol.flavanones50:against27–34.

methicillin-resistantStaphylo-230.Tyler,V.E.1987.Thenewhonestherbal.GeorgeF.StickleyCo.,Phila-delphia,Pa.

231.Urs,N.V.R.R.,andJ.M.Dunleavy.1975.Enhancementofthebactericidal

activityphaseoliofvar.asojensisperoxidase,soybeans).systemPhytopathologybyphenoliccompounds65:686–690.

(Xanthomonas232.U.S.DepartmentofHealthandHumanServices.1992.NationalToxicology

ProgramtechnicalreportonthetoxicologyandcarcinogenesisofcoumarininF344/NratsandB6C3F1mice(gavagestudies).NIHpublication92-3153.U.S.DepartmentofHealthandHumanServices,Washington,D.C.233.Vamos-Vigyazo,L.1981.Polyphenoloxidaseandperoxidaseinfruitsand

vegetables.Crit.Rev.FoodSci.Nutr.15:49–127.

234.VandenBerghe,D.A.,A.J.Vlietinck,andL.VanHoof.1986.Plantprod-uctsaspotentialantiviralagents.Bull.Inst.Pasteur84:101–147.

235.Vijaya,K.,S.Ananthan,andR.Nalini.1995.Antibacterialeffectoftheafla-vin,polyphenon60(Camelliasinensis)andEuphorbiahirtaonShigellaspp.—acellculturestudy.J.Ethnopharmacol.49:115–118.

236.Virus,R.M.,andG.F.Gebhart.1979.Pharmacologicactionsofcapsaicin:

apparentinvolvementofsubstancePandserotonin.LifeSci.25:1273–1284.

CLIN.MICROBIOL.REV.

237.Vishwakarma,artemisinin.J.Nat.R.A.Prod.1990.53:Stereoselective216–217.

synthesisof␣-arteetherfrom

238.Vlietinck,A.J.,andD.A.VandenBerghe.1991.Canethnopharmacology

contributetothedevelopmentofantiviraldrugs?J.Ethnopharmacol.32:141–153.

239.Vohora,S.B.,M.Rizwan,andJ.A.Khan.1973.Medicinalusesofcommon

Indianvegetables.PlantaMed.23:381–393.

240.Walker,C.B.1988.Microbiologicaleffectsofmouthrinsescontainingan-timicrobials.J.Clin.Periodontol.15:499–505.

241.Wan,J.,A.Wilcock,andM.J.Coventry.1998.Theeffectofessentialoils

ofscensbasil.J.onAppl.theMicrobiol.growthof84:Aeromonas152–158.

hydrophilaandPseudomonasfluore-242.Watanbe,H.,C.Miyaji,M.Makino,andT.Abo.1996.Therapeuticeffects

ofglycyrrhizininmiceinfectedwithLP-BM5murineretrovirusandmech-anisms220.

involvedinthepreventionofdiseaseprogression.Biotherapy9:209–243.Weiner,M.A.1980.Earthmedicine-earthfood:plantremedies,drugsand

naturalfoodsoftheNorthAmericanIndians.Macmillan,NewYork,N.Y.244.Weinmann,I.1997.Historyofthedevelopmentandapplicationsofcou-marinandcoumarin-relatedcompounds.InR.O’KennedyandR.D.Thornes(ed.),Coumarins:biology,applicationsandmodeofaction.JohnWiley&Sons,Inc.,NewYork,N.Y.

245.Wild,R.(ed.).1994.Thecompletebookofnaturalandmedicinalcures.

RodalePress,Inc.,Emmaus,Pa.

246.Xu,H.X.,F.Q.Zeng,M.Wan,andK.Y.Sim.1996.Anti-HIVtriterpene

acidsfromGeumjaponicum.J.Nat.Prod.59:643–645.

247.Ya,C.,S.H.Gaffney,T.H.Lilley,andE.Haslam.1988.Carbohydrate-polyphenolcomplexation,p.553.InR.W.HemingwayandJ.J.Karchesy(ed.),Chemistryandsignificanceofcondensedtannins.PlenumPress,NewYork,N.Y.

248.Yankauer,A.1997.Therecurringpopularityofalternativemedicine.Per-spect.Biol.Med.41:132–137.

249.Yao,X.-J.,M.A.Wainberg,andM.A.Parniak.1992.Mechanismof

inhibitionofHIV-1infectioninvitrobypurifiedextractofPrunellavulgaris.Virology178:56.

250.Yoshida,S.,S.Kasuga,N.Hayashi,T.Ushiroguchi,H.Matsuura,andS.

Nakagawa.1987.Antifungalactivityofajoenederivedfromgarlic.Appl.Environ.Microbiol.53:615–617.

251.Yoshikawa,M.,E.Harada,Y.Naitoh,K.Inoue,H.Matsuda,H.Shimoda,

J.Yamahara,andN.Murakami.1994.DevelopmentofbioactivefunctionsinHydrangeaedulcisfolium.III.OntheantiallergicandantimicrobialprinciplesofHydrangeaedulcisfolium.(1)ThunberginolsA,BandF.Chem.Pharm.Bull.(Tokyo)42:2225–2230.

252.Zafriri,D.,I.Ofek,R.Adar,M.Pocino,andN.Sharon.1989.Inhibitory

activityEscherichiaofcranberrycolitoeucaryoticjuiceoncells.adherenceAntimicrob.oftypeAgents1andChemother.typePfimbriated33:92–98.

253.Zhang,Y.,andK.Lewis.1997.Fabatins:newantimicrobialplantpeptides.

FEMSMicrobiol.Lett.149:59–64.