人工合成抗菌药3课件

人工合成抗菌药3Syntheticantimicrobial人工合成抗菌药3ClassificationQuinolonesSulfonamidesNitrofuransandnitroimidazole(Metronidazole)人工合成抗菌药3QuinolonesQuinolonesaresyntheticantimicrobialthatcontain4-quinoloneparentnucleus.人工合成抗菌药3ClassificationofquinolnesThefirst-generation(nalidixicacid,萘啶酸)

（1962）Thesecond-generation(pipemidicacid,吡哌酸)（1973）Thethird-generation-fluoroquinolones（1980s）Theforthgeneration-fluoroquinolones（theendof1990s）人工合成抗菌药3Thefirst-generation-nalidixicacid（1962）Oldermembersofthisclassofsyntheticantimicrobialagents,particularlynalidixicacid(萘啶酸),havebeenavailableforthetreatmentofurinarytractinfectionsformanyyears.Thesedrugsareofrelativelyminorsignificancebecauseoftheirlimitedtherapeuticutilityandtherapiddevelopmentofbacterialresistance.人工合成抗菌药3Thefirst-generation(nalidixicacid,萘啶酸)

（1962）Itiseffectiveforurinarytractinfectionsbecauseitconcentratedintheurine,

Narrowantibacterialspectrum:G-;PoorlyabsorbedHighadversereactionsIthasgoneoutofuse.

人工合成抗菌药3Thesecond-generation(pipemidicacid,吡哌酸)（1973）It’sactivityagainstgram-negativebacilliismorepowerful.Itisusedtreatingurinarytractandintestinalinfectionscausedbysusceptiblebacteria.人工合成抗菌药3Thethird-generation-fluoroquinolones（1980s）Itkilledawiderrangeoforganisms.Thegroupincludesnorfloxacin（诺氟沙星）ofloxacin（氧氟沙星）,ciprofloxacin(环丙沙星),andothers.theyarebactericidal.

人工合成抗菌药3Fluoroquinolones人工合成抗菌药3FirstgenerationSecondgenerationThirdgenerationnalidixicacidGram-negativebacteriathatcauseurinarytractinfections,theirintrinsicactivityislimited.norfloxacinciprofloxacinofloxacinBroadspectrumandmorepotent.sparfloxacinBroaderspectrum,especiallygram-positivebacteriaandanaerobicmicroorganisms.Morepotent.Other:Chlamydia,Mycoplasma,Legionella,Mycobacterium.Pharmacologicalpropertiesofdifferentquinolones人工合成抗菌药3AntibacterialactivityFluoroquinolonesareactiveagainstgram-negativeorganismsincludingEscherichiaSalmonella,Shigella,Pseudomonasaeruginosa,andHemophilusinfluenzae.Gram-positiveorganisms(staphylococci,diplococcuspneumoniaeandstreptococcusetc.)andintracellularpathogensareinhibitedbysomewhathigheramountsofthesedrugs.Fluoroquinolonesarealsoactiveagainstatypicalpneumonia(非典型肺炎（atypicalpneumonia）,是指由病毒、支原体、衣原体、立克次体和军团菌等引起的肺炎，其症状表现相对于典型肺炎而言不典型。)(e.g.,mycoplasmas支原体andchlamydiae[klə'midii:]衣原体)andintracellularpathogenssuchasMycobacteriumtuberculosis.[maikəubæk’tiəriəm]

[tubə:kjə’ləusis],

人工合成抗菌药3MechanismofactionInhibitingtypeIItopoisomerases(DNAgyrase)andtopoisomeraseIV人工合成抗菌药31.2MechanismofactionQuinolonesenterthecellbypassivediffuse.Intracellularly(细胞内的),

theyinhibitthesynthesisofbacterialDNAbyinterferingwiththeactionofDNAgyrase(DNA回旋酶，topoisomerase拓扑异构酶ⅡorⅣ).人工合成抗菌药31.2MechanismofactionThetwostrandsofdouble-helicalDNAmustbeseparatedtopermitDNAreplicationortranscription.However,anythingthatseparatesthestrandsresultsin"overwinding"orexcessivepositivesupercoilingoftheDNAinfrontofthepointofseparation.Tocombatthismechanicalobstacle,thebacterialenzymeDNAgyraseisresponsibleforthecontinuousintroductionofnegativesupercoilsintoDNA.ThisisanATP-dependentreactionthatrequiresthatbothstrandsoftheDNAbecuttopermitpassageofasegmentofDNAthroughthebreak;thebreakisthenresealed.人工合成抗菌药31.2MechanismofactionModeloftheformationofnegativeDNAsupercoilsbyDNAgyrase.(1)Anodeofpositiveiscreatedfor(+)superhelix.(2)Theenzymeintroducesadouble-strandbreakintheDNAandpassesthefrontsegmentthroughthebreak.(3)Thebreakisthenresealed,creatinganegative(-)supercoil.Quinolonesinhibitboththenickingandclosingactivityofthegyrase.人工合成抗菌药3人工合成抗菌药3人工合成抗菌药31.2MechanismofactionTheDNAgyraseofE.coliiscomposedoftwo105,000-daltonAsubunitsandtwo95,000-daltonBsubunits.TheAsubunits,whichcarryoutthestrand-cuttingandresealingfunctionofthegyrase,arethesiteofactionofthequinolones.人工合成抗菌药31.2MechanismofactionAABB••BindingsitesofquinolonesATP-ATP-人工合成抗菌药3Onlyforbacteria

the

DNAgyraseThoughtheyhavesimilarfunction,butthestructurearedifferent,theDNAtopoisomerase拓扑异构酶Forhumanoranimalthe

DNAgyrasedoesn’tactonhumanoranimal人工合成抗菌药3人工合成抗菌药3PharmacokineticsWellabsorptionafteroraladministrationanddistributionwidelyinbodyfluidsandtissues.TherelativelylongT1/2Renalclearancepredominatesformostfluoroquinolones.人工合成抗菌药3ResistanceCrossresistanceamongthedrugsofthisclass；Commondrug-risistancebacteria:Staphylococcusaureus,enterococcus,Escherichiacoliand

Pseudomonasaeruginosa

etc.人工合成抗菌药3MechanismofresistanceMutationsinthebacterialchromosomalgenesencodinggyrA,ortopoisomeraseIV.Achangeinthepermeabilityoftheorganism;e.g.EscherichiacoliActivetransportofthedrugoutofthebacteria

;e.g.

Staphylococcusaureus人工合成抗菌药3ClinicalapplicationUrinarytractinfections:urethritis,cervicitis,prostatitis.thefirstchoiceisciprofloxacin,gatifloxacinorofloxacinRespiratoryinfectionsIntestinalinfectionandtyphusBone,joint,skin,parenchyma,surgery,E.N.Tinfections.人工合成抗菌药3AdversereactionGastrointestinaleffectsCNSreaction：excitedSkinandphotosensitivityCartilagedamageLiverorrenalfunctionallesion，Achillestendinitis，hearttoxicity，eyetoxicity.人工合成抗菌药3Contraindication['kɔntrə,indi'keiʃən]禁忌症

Children,pregnantwomen,sucklingwomen,insanepatientorpatientofepilepsyhistoryAllergicpatient

人工合成抗菌药3CommonfluoroquinolonesinclinicNorfloxacin诺氟沙星(氟哌酸itsabsorptionisaffectedbyfood.（35-45%）LowplasmadrugconcentrationHighurineandintestinaltractdrugconcentrationNoclinicalvalueformycoplasma,chlamydia,legionella人工合成抗菌药3Ciprofloxacin

[,siprəu'flɔksəsin]环丙沙星ThestrongestantibacterialactioninvitroBioavailabilityis38-60%StrongeffectforG-bacillianddrug-resistanceG+/G–TherapeuticapplicationismainlyforinfectionsofotherdrugresistanceG-bacilli.Noeffectformostanaerobian.

人工合成抗菌药3ThesameantibacterialcharactertociprofloxacinInaddition,ofloxacinhaseffectformycobacteriumtuberculosis,chlamydiatrachomatisandsomeanaerobian.Thesecond-lineagentfortreatmentoftuberculosisLevofloxacinItsantibacterialactivityisdoubleofofloxacin’s.

Ofloxacin氧氟沙星

人工合成抗菌药3

goodabsorptionbyoraladministrationItsbioacailabilityisabout99%.DistributedwidelyinbodyfluidsandtissuesStrongantibacterialactivityinvivoAdversereactionismore.Fleroxacin氟罗沙星

人工合成抗菌药3ⅡSulfonamides

Trimethoprim人工合成抗菌药3IntroductionThesulfonamidedrugswerethefirsteffectivechemotherapeuticagentstobeemployedsystemicallyforthepreventionandcureofbacterialinfectionsinhumanbeings.Theadventofpenicillinandotherantibioticshasdiminishedtheirusefulness,andtheyarelessfrequentlyprescribedforatime.However,theintroductioninthemid-1970softhecombinationoftrimethoprimhasresultedinincreaseduseofsulfonamidesforthetreatmentofspecificmicrobialinfections.人工合成抗菌药32.1AntibacterialspectrumTheyarebacteriostatic.Generally,theyarebroad-spectrumagentsthatareeffectiveagainstgram-positiveandgram-negativeorganisms.人工合成抗菌药32.2MechanismofactionSulfonamidesarestructuralanalogsofpara-aminobenzoicacid(PABA)andactascompetitiveinhibitorsofdihydropteroatesynthase(二氢蝶酸合成酶）andpreventthesynthesisofbacterialfolicacid.Trimethoprim(TPM)preventsthereductionofdihydrofolatetotetrahydrofolatebyinhibitingdihydrofolatereductase.人工合成抗菌药32.2MechanismofactionWhentwodrugareusedincombination,antimicrobialsynergyresultsfromthesequentialblockadeoffolatesynthesis.Thedrugcombinationissometimesbactericidalagainstsusceptibleorganisms.Sulfamethoxazole(SMZ磺胺甲噁唑，新诺明)isthesulfonamideusedincombinationwithtrimethoprimbecausetheyhavematchinghalf-lives.人工合成抗菌药32.3TherapeuticapplicationsSystemicinfections:SMZgiventogetherwithTMP,isusedwidelyforrespiratorytractandentericinfections.Sulfadiazine(SD,磺胺嘧啶）achievestherapeuticconcentrationsincerebrospinalfluidandisafirst-linetherapyfortreatmentofepidemiccerebrospinalmeningitis.

Localinfections:Sulfasalazine(柳氮磺吡啶)ispoorlyabsorbedfromt