-药物微生物与宿主化学疗法的元素(英文)DrugsMicrobes-Host-The-Elements-of-课件

Drugs,Microbes,Host–TheElementsofChemotherapyChapter12

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inthewhitebackgroundbeforeyouadvancethenextslide.Antibiotics-StillMiracleDrugs3Abriefhistoryofantibiotics1495,mercurytotreatsyphilis.1630,quinine(chinchonatree)formalarialfeverbySouthAmericanIndians.1910,PaulEhrlichdevelopedarsenicalcompound(Salvarsan)forsyphilis,term:thechemicalknife.1929,AlexanderFlemingfoundpenicillin.1940,ErnstChainandHowardFlorydemonstratedtheeffectofpenicillin.1940-1970,searchfornewantibioticsRecentyears:modifyingolddrugs,findingnewdisciplineincombatingantibioticsresistanceForlectureonlyBCYangHistoricalPerspective100yearsago-1in3childrendiedofinfectiousdiseasebeforeage5GermtheoryofdiseaseKoch’spostulatesRobertEhrlich-microbespecificdyesSirAlexanderFlemming-discoveredpenicillin(1929)PaulEhrlich’s“MagicBullet”ConceptSalvarsanNo.606PlateofStaphylococcusaureusinhibitedbyPenicilliumnotatumFlemmingandPenicillinPrinciplesofAntimicrobialTherapyGoalofantimicrobialchemotherapy:administeradrugtoaninfectedperson,whichdestroystheinfectiveagentwithoutharmingthehost’scellsRatherdifficulttoachievethisgoalChemotherapeuticagentsdescribedwithregardtotheir:originrangeofeffectiveness

naturallyproducedorchemicallysynthesized

AntibioticsTopics -AntimicrobialChemotherapy -SelectiveToxicity -SurveyofAntimicrobialDrugs -MicrobialDrugResistance -DrugandHostInteraction

TheOriginsofAntimicrobialDrugsAntibiotics~metabolicproductsofaerobicbacteriaandfungi~reducecompetitionfornutrientsandspaceBacteria:Streptomyces,AcromycesandBacillusMolds:PenicilliumandCephalosporiumChemistshavecreatednewdrugsbyalteringthestructureofnaturallyoccurringantibioticsSelectiveToxicityDrugsthatspecificallytargetmicrobialprocesses,andnotthehumanhostcellularprocesses.SelectiveToxicity

MechanismsandsitesMechanismofactionBacterialcellwallNucleicacidsynthesisProteinsynthesisCellmembraneFolicacidsynthesisTargetsofAntimicrobials1.CellwallinhibitorsBlocksynthesisandrepair Penicillins Cephalosporins Carbapenems Vancomycin Bacitracin Fosfomycin Isoniazid2.CellmembraneCauselossofselectivepermeability Polymyxins Daptomycin3.DNA/RNAInhibitreplicationandtranscription Inhibitgyrase(unwindingenzyme) Quinolones InhibitRNApolymerase RifampinRibosomemRNADNA4.ProteinsynthesisinhibitorsactingonribosomesSiteofaction50SsubunitErythromycinClindamycinSynercidPleuromutilinsSiteofaction30SsubunitAminoglycosidesGentamicinStreptomycinTetracyclinesGlycylcyclinesBoth30Sand50SBlocksinitiationofproteinsynthesisLinezolid5.FolicacidsynthesisBlockpathwaysandinhibitmetabolismSulfonamides(sulfadrugs)TrimethoprimSubstrateEnzymeProductMechanismsofDrugActionInhibitionofcellwallsynthesisInhibitionofnucleicacidstructureandfunctionInhibitionofproteinsynthesisInterferencewithcellmembranestructureorfunctionInhibitionoffolicacidsynthesisAntibioticsthatblockCellwallsynthesisPenicillinandCephalosporins

are

β-lactamantibiotics.NotveryeffectiveagainstGrampositivebacteriaActivecellsmustconstantlysynthesizenewpeptidoglycanandtransporttocellenvelope.

PenicillinsandCephalosporinsreactwithoneormoreoftheenzymesrequiredtocompletethisprocess.(blockstranspeptidasesinvolvedincross-linkingtheNAGNAMsugars)Abacteriumdamagedanddistortedbypenicillin

Themechanismofactionofpenicillinsandcephalosporins.

β-Lactamantibioticsbindtoandcompetitivelyinhibitingthetranspeptidaseenzymethatcross-linksPGlayers.Wehavecomealongway!Penicillinwasbeingmass-producedby1944.PenicillinSource:PenicillinchrysogenumPenicillinantibioticsgroupedintogenerationsbasedonspectrumofanti-microbialactivity.(1st,2nd,3rdand4thgenerations)Natural(penicillinGandV)Semisynthetic(Ampicillin,Carbenicillin)β-lactamantibioticsTheseallshareacommonβ-lactamring,showninblue-TheRgroupisresponsiblefortheactivityofthedrugandcanbechangedtoimproveactivityoftheantibiotic.

-Cleavageofthebeta-lactamringwillrenderthedruginactive...bacteriahavefiguredthisout!.ChemicalstructureofpenicillinsStructureThiazolidineringBeta-lactamringVariablesidechain(Rgroup)Penicillinresistance

viapenicillinase(bLactamase)SomepenicillinresistantorganismsproducePenicillinasewhichdegradespenicillin.Methicillin

(β-lactamantibiotic)Developedtotreat,β-lactamaseproducingorganismssuchasStaphylococcusaureusMRSAquicklyevolvedMethicillinunstableingastricacid-discontinuedCephalosporin

(b-LactamAntibiotic)Cephalosporiumacremonium(mold)WidelyadministeredtodayDiversegroup(naturalandsemisynthetic)1st,2nd,and3rdgenerationsStructuresimilartopenicillinexceptMainringisdifferentTwositesforRgroupsThedifferentRgroupsallowforversatility

andimprovedeffectiveness.Thestructureofcephalosporins

Antibioticsweakenthecellwall,causethecelltolyse.AntibioticsthatblockCellwallsynthesis

-effectiveagainstMethicillinResistantStaphylococcusaureus(MRSA)-Vancomycinisabroad-spectrumantibioticandoftenusedaftertreatmentwithotherantibioticshavefailedVancomycin–hinderspeptidoglycanelongationAntibioticsthatblockcellwallsynthesisCycloserine–inhibitstheformationofthebasicpeptidoglycansubunits-aminoacidanalog-effectiveagainstMycobacteriumtuberculosisBacitracin

–InhibitsthetransportofNAGandNAMacrossthecellmembraneinthesynthesisofpeptidoglycan-Toxicitylimitsoraluse-commoningredientofeyeandskinantibioticpreparationsInhibitionofProteinsynthesis-Proteinsynthesisinhibitorsgenerallybroadspectrum,toxicityproblems.Inhibitorsof50SribosomalsubunitChloramphenicolBindstothe50SribosomePreventspeptidebondformationMacrolidese.g.ErythromycinBindstothe50SribosomePreventspeptidebondformationChloramphenicolInhibitsproteinsynthesisBroad-spectrumBacteriostaticTreattyphoidfever,brainabscessesRarelyusednowduetoserioussideeffects–aplasticanemiaErythromycinInhibitsproteinsynthesisBroad-spectrumCommonlyusedasprophylacticdrugpriortosurgerySideeffects-lowtoxicityExamplesAminoglycosides(Streptomycin,neomycin,gentamycin)

Bindtothe30SribosomeCausesMisreadingofmRNATetracyclines

-BlockattachmentoftRNAInhibitorsof30SribosomalsubunitAminoglycosidesFromStreptomycesInhibitproteinsynthesisStreptomycessynthesizesmanydifferentantibioticssuchasaminoglycosides,tetracycline,chloramphenicol,anderythromycin.TetracyclineInhibitsproteinssynthesisBroadspectrumandlowcostCommonlyusedtotreatsexuallytransmitteddiseasesMinorsideeffect–gastrointestinaldisruptionAminoglycoside SitesofinhibitionontheprocaryoticribosomePolymyxinB-BactericidaltomostGramnegatives-DisruptscellmembraneandmakesitmorepermeableTopicalONLY-NeurotoxicCombinedwithbacitracinandneomycin(broadspectrum)inover-the-counterpreparation(Neosporin)InjurytothePlasmaMembraneRifamycinBindstoprokaryoticRNAPolymeraseandinhibitsRNAsynthesisAntituberculosisQuinolonesandfluoroquinolonesCiprofloxacinSeriousadverseeventsoccurmorecommonlywithfluoroquinolonesthanwithanyotherantibioticdrugclasses.InhibitsDNAgyraseUrinarytractinfectionsInhibitorsofNucleicAcidSynthesisFolicacidsynthesis

(vitaminB9)Sulfonamides(sulfadrug)andtrimethoprimSyntheticanalogsCompetitiveinhibitionofkeyenzymesPreventsthemetabolismofDNA,RNA,andaminoacidSulfaallergiesarecommonprescribedcarefullySulfonamidescompetewithPABAfortheactivesiteontheenzyme.ThesulfonamideSulfamethoxazoleiscommonlyusedincombinationwithtrimethoprim.FolicacidisessentialtosynthesizeDNA,repairDNA,andmethylateDNA…Goodtarget!Broadvs.narrowspectrumdrugsAntiviralsIncreasingtypesofdrugsbecomingavailableHowever,itisdifficulttomaintainselectivetoxicity

AugmentHostSelf-DefenseSystemInterferon–geneticallyengineeredantiviralproteinfromahumangeneVaccinesAntiviralsUnlikemostantibiotics,antiviraldrugsdonotdestroytheirtargetpathogen-insteadtheyinhibittheirdevelopment.EffectivedrugstargetviralinfectionandreplicationcycleEntryNucleicacidsynthesisAssembly/releaseAntiviralsMostantiviralsnowavailabletarget:-

HIV-herpesvirus-hepatitisBandC-influenzaAandBvirusesAnti-viralresistantstrainsexistAntiviraldrugstructuresandtheiruniquemodesofaction.Antiviraldrugstructuresandtheiruniquemodesofaction.Antiviraldrugstructuresandtheiruniquemodesofaction.OthertypesofantimicrobialsAntifungal–ketoconizoleAntiprotozoan–metronidazoleTreatgiardiasisAntimalarial–QuininePlasmodiumfalciparummalariaAntihelminthic–mebendazoleTapeworms,roundwormsGiardiaAntimicrobialResistanceRelativeorcompletelackofeffectofantimicrobialagainstapreviouslysusceptiblemicrobeEnzymaticdestructionofdrugPreventionofpenetrationofdrugAlterationofdrug'stargetsiteRapidejectionofthedrugMechanismsofAntibioticResistanceMechanismsofAntibioticResistanceWaystoacquireresistanceFigure20.20AntibioticResistanceFigure20.20AntibioticResistanceIntermicrobialtransferofplasmidscontainingresistancegenes(Rfactors)occursbyconjugation,transformation,andtransductionWhatFactorsPromoteAntimicrobialResistance?Exposuretosub-optimallevelsofantimicrobialInappropriateuseExposuretomicrobescarryingresistancegenesInappropriateAntimicrobialUsePrescriptionnottakencorrectlyAntibioticsforviralinfectionsAntibioticssoldwithout medicalsupervisionSpreadofresistantmicrobes inhospitalsduetolackofhygieneInappropriateAntimicrobialUseInadequatesurveillanceordefectivesusceptibilityassaysPovertyorwarUseofantibioticsinfoodsLackofqualitycontrolinmanufactureoroutdatedantimicrobialAntibioticsinFoodsAntibioticsareusedinanimalfeedsandsprayedonplantstopreventinfectionandpromotegrowthMultidrug-resistantSalmonellatyphihasbeenfoundin4statesin18peoplewhoatebeeffedantibioticsAntibioticDrugandHostInteractionToxicitytoorgansAllergicreactionsSuppress/altermicrofloraEffectivedrugsTetracyclinetreatments

cancauseteethdiscoloration.Disruptingthenormalfloraintheintestinecanresultinsuperinfections.FindinganeffectivedrugfortrreatmentIdentifyinfectiousagentPerformsensitivitytestingOftentheMinimumInhibitoryConcentration(MIC)isdetermined

The