說明教案成果introduction of antimicrobial agents

YiYangSectionVIII

ChemotherapeuticDrugs

Drugsfortreatmentofcancerandinfectiousdiseasescausedbybacteriaorothermicrobes(virus,fungi),andevenparasites,etc.Antimicrobial(Antibacterial,Antifungal,Antiviralagents)ChemotherapeuticDrugsDefinitionandCharacteristicsAntibacterialagents(ABAs) ThesubstancesusedagainstinfectiousdiseasesbyinhibitingorkillingthepathogenicbacteriaAntibioticsAntibacterialsubstancesproducedbyvariousspeciesofmicroorganisms(bacteria,fungi,andactinomycetes)thatsuppressthegrowthofothermicroorganisms.Syntheticantimicrobialagents

sulfonamidesandquinolones

Antibacterialaction(1)AntibacterialSpectrumNarrowSpectrumABAs：IsoniazidBroadSpectrumABAs：Tetracyclines,ChloramphenicolsG+G-TBCMRL(2)AntibacterialActivity

ActivityofABAstoinhibitorkillcertainbacteriaEvaluationInVitro：minimalinhibitoryconcentration(MIC)minimalbactericidalconcentration(MBC)InVivo：experimentaltherapyBacteriostaticAgents

Tetracyclines,ErythromycinsBactericidalAgents

Penicillins,Cephalosporins,Aminoglycosides,QuinolonesInhibitingoreliminatingbacteriaisalsodependentonABAs’doseandtimeofaction.Resistance

TheabilityofbacteriatowithstandanABAtowhichtheywereoncesensitiveAbove90％strainsofStaphylococcusA.aremethicillin-resistant!Safety

Idealchemotherapeuticagentsshouldhavepowerfulantibacterialactivityandtrivialtoxicitytohumanbody.ChemotherapeuticIndex(CI)

＝LD50/ED50orLD5/ED95

HigherCIcorrelateswithgreatertherapeuticeffectandlowertoxicity.Exception：Penicillincausesallergicshockin1/60000cases.ClassificationAntimicrobialagents(bychemicalstructureandproposedmechanismofaction)Agentsthatinhibitsynthesisofbacterialcellwallsbeta-lactam(e.g.,penicillins,cephalosporins,andcarbapenems)ycinAgentsthatactdirectlyonthecellmembraneofthemicroorganism(permeabilityandleadingtoleakageofintracellularcompounds)detergentssuchaspolymyxinpolyeneantifungalagents(e.g.,nystatinandamphotericinB)Agentsthatreversiblyinhibitproteinsynthesis(disruptfunctionof30Sor50Sribosomalsubunits)Bacteriostaticchloramphenicol,thetetracyclines,erythromycin,clindamycin,streptogramins,andlinezolidAgentsthatalterproteinsynthesis(bindtothe30Sribosomalsubunit)BactericidalaminoglycosidesAgentsthataffectbacterialnucleicacidmetabolismQuinolones(inhibittopoisomerases)AntimetabolitesSulfonamides(blockessentialenzymesoffolatemetabolism)AgentsthatinhibitsynthesisofbacterialcellwallsBasicstructureofpeptidoglycan(1)InhibitsynthesisofbacterialcellwallsPenicillininhibitcrosslinkofpeptidoglycanstrands→defectofcellwalls→swellinganddeformation→lysisandbreakdownofbacteriaAgentsthatactdirectlyonthecellmembrane(2)IncreasethepermeabilityofcellmembranePolymyxinbindstophospholipids→membranepermeability↑→leakageofintracellularcompounds→deathofbacteriaAgentsthatreversiblyinhibitproteinsynthesisRibosome核糖體大亞基50S30S70SAPRAP(3)InhibitsynthesisofproteinsAminoglycosidesbindtothe30Sribosomalsubunit→alterproteinsynthesis→bactericideErythromycinbindstothe50Sribosomalsubunit→inhibitsproteinsynthesis→bacteriostasisDifferentribosomalstructurebacteria：70S(prokaryoticcell)30S+50Shuman：80S(eukaryoticcell)40S+60Snoeffectonhumanproteinsynthesis(4)AffectnucleatemetabolismRifampinbindstoDNA-dependentRNApolymerase→inhibitionofmRNAsynthesisQuinolonesbindtoDNAgyraseandtopoisomeraseⅣ→inhibitionofDNAreplicationandtranscriptionAgentsthataffectbacterialnucleicacidmetabolism(5)AntagonizefolatemetabolismAntimetabolites

GlutamicAcidFood+dihydrofolatesynthasedihydrofolatereductase

dihydropteridine

dihydrofolatetetrahydrofolicacid+PABA

onecarbonunit

synthesisofDNA/RNA↑sulfinamides↑trimethoprim(5)AntagonizefolatemetabolismSulfonamidesbindtodihydrofolatesynthase,trimethoprimbindtoreductase→inhibitionofDNAsynthesisClassificationCellwallCytoplasmMechanismsofactionofantimicrobialagentsproteininhibitsynthesisofbacterialcellwallsactdirectlyonthecellmembraneinhibitproteinsynthesisaffectbacterialnucleicacidmetabolismAntimetabolitesDrugresistanceareacquiredby…MutationSelectionWildtypeMutantImpaireddefensesIntactdefensesInfectionisremovedworseMICHowareresistancegenestransferred?HorizontalgenetransferBymobileelements:plasmidandtransducingphagesTransductionTransformationConjugationBacterialresistancetoantimicrobialagentsThedrugdoesnotreachitstarget

Absenceof,mutationin,orlossofafavoredporinMutationoftransporterEffluxpumpsThedrugisnotactiveThetargetisaltered

(1)reducethepermeabilityofoutermembrane

Porinsareresponsiblefortheentryortransportationofsomedrugsintobacteria.Changeofcomponents,amount,andfunctionofporinsinG-bacillusvs.aminoglycosidesNovelporeblockerinbacteriavs.tetracyclinesThedrugdoesnotreachitstarget(2)activeeffluxsystemEscherichiacoli,StaphylococcusA.,PseudomonasA.,CampylobacterJ.,etalpumpoutb-lactams,quinolones,tetracyclines,chloramphenicolsThedrugdoesnotreachitstarget(3)productionofdrug-inactivatingenzymesG+bacteriaproduceb-lactamasetohydrolyzeb-lactamofpenicillinG-bacillusproducemodifyingenzymetocatalyzethebindingofsomechemicalgroupsto–OH,-NH2ofaminoglycosidesThedrugisnotactive(4)targetalterationDrug-targetaffinity↓：b-lactams-PBPs↓Changeoftargetstructure：

PBP2vs.methicillin(MRSA)novelP10proteinvs.streptomycinnovelRNApolymerasebsubunitvs.rafimpinThetargetisaltered(5)othermechanismMetabolicantagonist↑：MorePABAsareproducedtocompetewithsulfonamidesbindingtoDHFS

GlutamicAcidFood+dihydrofolatesynthasedihydrofolatereductase

dihydropteridine

dihydrofolatetetrahydrofolicacid+PABA

onecarbonunit

synthesisofDNA/RNA↑sulfinamides↑trimethoprimThroughheredityorcontact,bacterialosesusceptibilitytoABAsbychangingstructureoffunctionalmolecules,metabolismpathways,orproducingneutralizers,makingitmoredifficulttocontaintheinfection.AbuseofABAsisresponsibleforthebigtroub