抗生素作用机理

抗生素作用机理夏海洋hyxia@抗生素(antibiotics)●微生物在代谢过程中产生的，在低浓度下就能抑制它种微生物的生长和活动，甚至杀死它种微生物的化学物质。如青霉素、链霉素和金霉素等两点补充：1、来源方面，不再局限于微生物生产；

2、性能方面：不再局限于抗细菌，抗肿瘤、抗原虫、抗病毒、抗寄生虫、杀虫除草等。Asubstanceofbiological,semisyntheticorsyntheticoriginoflowmolecularweight(on-protein)producedbyafungusorbacteriumassecondarymetabolitesthatinhibitsorstopgrowthofothermicroorganismsinvitroandinvivoselectively,whenitusedinlowconcentrationPrincipaltargetsforantibioticactionNatureReviewsMicrobiology1,65-70MolecularSystemsBiology3:142ribosomeforaminoglycosidesDNAgyraseforquinolonepenicillin-bindingproteinsforβ-lactamTheproposedmechanismofactionforcationicpeptideshttp://www.scq.ubc.ca/β-LactamsBindingtopenicillin-binding-protein(PBP)

innercellmembraneendogeneousbacterialautolysis

Activitydependon:(1)PBPtype(2)degreeofaffinitytoaparticularPBPMechanismofAntimicrobialActivityofBacitracin

Itformschelateswithheavymetals.EDTAdeactivatesit,So:DivalentionssuchasZn2+arenecessaryfortheantimicrobialactionofBacitracin.Itinhibitsthebiosynthesisofpeptidoglycanofthebacterialcellwallbyinhibitionofdephosphorylationofphospholipid.PolymyxinBGramicidineItisobtainedbyextractionfromtyrothricin,amixtureoftwopolypeptidesisolatedfromBacillusbrevis.Tyrothricinisconsistedofgramicidinsandtyrocidins.GramicidinisamixtureofA1,A2,A3,B1,B2andC.Gramicidinismoreeffectiveantibacterialintyrothricinmixture.Itactsasanionophoreinthebacterialcellwallandmakesaholeinit:Bactericidal.ActiveagainstG(+)bacteria.SpectrumofactivityActiveagainstG(+)bacteria.Itisusedonlylocally,systemicadministrationcauseserythrocytemembranelysis.Itcannotbeadministeredonopenwounds.MechanismofActionItactsasanionophoreinthebacterialcellwallandmakesaholeinit:Bactericidal.IonophoresIonophoresareagentsthatenterthecellmembraneandchangeitspermeability.Theymaketheionsmoveinwardandoutwardofthecellmembrane,sotheionconcentrationswillbecomeequalinbothsides.Therearetwotypesofionophores:Thosewhichmakeaholeinthecellmembranewhichpermitstheionstomoveupongradientofconcentration:GramicidinandTyrotricin.Thosewhichcarrycationsfromonesidetotheothersideofthecellmembrane:Valinomycinandsyntheticmoleculessuchascrownethersandcryptates.GramicidinasanionophoreTwomoleculesofgramicidinmakeachannelinthebacterialcellmembrane,N-terminalsmeetinthemiddleofthemembraneandC-terminalsareoutsideit.Eachgramicidinmoleculeisintheformofaleft-handedhelix,whichresultsinthepolargroupsliningtheinteriorofthechannel.Thisfacilitatesthetransferofpolarionsthroughthechannel.Asinglegramicidinchannelcanallowthetransportofupto107K+ionspersecond.IonchannelofthegramicidinAchannel.Thechannelisrepresentedbyasurfacethatiscolor-codedaccordingtothelipophilicpotential(blue:hydrophilic,red:lipophilic).CarrierIonophoresCarrierionophoresarespecificforparticularions.ValinomycinwilltransportK+butnotNa+orLi+.Itformsanoctahedralcomplexwithsixcarbonyl-groupoxygenatomsactingasligands.Theresultingcomplexhasahydrophobicexterior,whichallowsthecomplextodiffusethroughthemembrane.TherigidnatureofthemoleculecoupledwithitssizemakesthebindingsiteofittoolargetoformcomplexeswithNa+orLi+.ValinomycinTyrocidinTyrocidinItisextractedfromtyrothricinasamixtureoftyrocidinA,B,C,D.Itactsasanionophoreinthebacterialcellwallandmakesaholeinit:Bactericidal.ActiveagainstG(+)bacteria.Itisusedonlylocally,systemicadministrationcauseserythrocytemembranelysis.Itcannotbeadministeredonopenwounds.AntibioticsthatInhibitProteinSynthesisReviewofInitiationofProteinSynthesis30S132GTP123GTPInitiationFactorsmRNA312GTP30SInitiationComplexf-met-tRNASpectinomycinAminoglycosides12GDP+Pi50S70SInitiationComplexAPAminoglycosides(bactericidal)

streptomycin,kanamycin,gentamicin,tobramycin,amikacin,netilmicin,neomycin(topical)Modeofaction-Theaminoglycosidesirreversiblybindtothe16SribosomalRNAandfreezethe30Sinitiationcomplex(30S-mRNA-tRNA)sothatnofurtherinitiationcanoccur.TheyalsoslowdownproteinsynthesisthathasalreadyinitiatedandinducemisreadingofthemRNA.Bybindingtothe16Sr-RNAtheaminoglycosidesincreasetheaffinityoftheAsitefort-RNAregardlessoftheanticodonspecificity.Mayalsodestabilizebacterialmembranes.Interferingwithproteinsynthesisduringaerobicmetabolism.Goodpotensy:concentration-dependentkillingeffectandtime-dependentPAEonG(+)andG(-)organismsPotencydependon1)susceptibilitytoaminoglycoside-inactivatingenzyme2)permeabilitytocellwallAminoglycosidesBindingpocketofgentamicinintheA-siteRNATheEMBOJournal(1998)17,6437–6448FreezeinitiationBlockpeptidebondformationMisreadingofmRNAReviewofElongationofProteinSynthesisGTPAPTuGTPTuGDPTsTsTu+GDPTsPiPATetracyclineAPErythromycinFusidicAcidChloramphenicolGGTPGGDP+PiGGDPAP+GTP①Chloramphenicol②Clindamycin

Macrolides③TertracyclinesTetracyclines

(bacteriostatic)

tetracycline,minocyclineanddoxycyclineModeofaction-Thetetracyclinesreversiblybindtothe30Sribosomeandinhibitbindingofaminoacyl-t-RNAtotheacceptorsiteonthe70Sribosome.Spectrumofactivity-Broadspectrum;Usefulagain