簡介:抗菌藥物抗菌藥物的抗菌類型及抗菌機(jī)理細(xì)菌的耐藥性細(xì)菌的耐藥機(jī)理細(xì)菌耐藥性的控制策略,抗菌藥物,ANTIBIOTICS(抗生素),其他抗菌物BACTERIOPHAGE(噬菌體)BACTERIOCIN(細(xì)菌素)LYSOZYME(溶菌酶),ANTIBIOTICS抗生素,■ANTIBIOTICS(抗生素)由真菌、放線菌或細(xì)菌自然代謝產(chǎn)生的可殺死或抑制微生物生長的物質(zhì)■SYNTHETICANTIBIOTICS(合成抗生素)在實驗室中,通過化學(xué)合成生產(chǎn)的可殺死或抑制微生物生長的物質(zhì),DISCOVERY,■PENICILLINTHEFIRSTNATURALANTIBIOTICSPRODUCEDBYPENICILLIUMNOTATMIDENTIFIEDBYALEXANDERFLEMINGIN1928,,ALEXANDERFLEMMING,ACQUIREDNOBLEPRIZEIN1945,■PENCILLINWASPURIFIEDANDTESTEDINMICESHOWINGITSTHERAPEUTICACTIONAGAINSTLETHALBACTERIAINFECTIONIN1935BYHOWARDFLOREYANDEMSTCHAINALEXANDERFLEMMINGHOWARDFLOREYACQUIREDNOBLEPRIZEIN1945EMSTCHAIN,,STREPTOMYCINWASIDENTIFIEDBYSELMANWAKSMANIN1944ACQUIREDNOBLEPRIZEIN1952LARGESCALEPRODUCTIONOFPENICILLINBYUSPHARMACEUTICALCOMPANIESINEARLY1940S,■HUNDREDSANDTHOUSANDSOFLIVEOFINFECTEDSOLDIERSWERESAVEDBYTHEENDOFWWII■SCREENINGANDDISCOVERIESOFMANYOTHERKINDSOFANTIBIOTICSIN1950SAND1960S■MICROBESBEGANDEVELOPINGRESISTANCEAGAINSTTHEWONDERDRUGS,抗生素的種類,PENICILLINS青霉素類ΒLACTAMSCEPHALOSPORINS頭孢菌素類AMINOGLYCOSIDES氨基糖甙類TETRACYCLINS四環(huán)素類MACROLIDES大環(huán)內(nèi)酯類POLYMYXINS多粘菌素類QUINOLONES喹諾酮類RIFAMYCINS利福霉素類SULPHONAMIDES磺胺類,,,ΒLACTAMSΒ內(nèi)酰胺類),,ΒLACTAMSΒ內(nèi)酰胺類),PENICILLINS青霉素類PENICILLING(青霉素G)AMPICILLIN(氨芐西林)AMOXICILLIN(阿莫西林)CEPHALOSPORINS頭孢菌素類CEFALOTHIN頭孢噻吩,先鋒I(第一代CEFOTIAM頭孢替安(第二代CEFOTETAN頭孢他定,復(fù)達(dá)欣(第三代,,,AMINOGLYCOSIDES氨基糖甙類,STREPTOMYCIN鏈霉素GENTAMICIN慶大霉素KANAMYCIN卡那霉素AMIKACIN丁胺卡那霉素,阿米卡星)TOBRAMYCIN妥布霉素,TETRACYCLINS四環(huán)素類,TETRACYCLINE四環(huán)素TERRAMYCIN土霉素DOXYCYCLINE強力霉素,MACROLIDES大環(huán)內(nèi)酯類,ERYTHROMYCIN紅霉素MIDECAMYCIN麥迪霉素ACETYLSPIRAMYCIN乙酰螺旋霉素,POLYMYXINS多粘菌素類,POLYMIXINBPOLYMIXINE,QUINOLONES喹諾酮類,NORFLOXAXIN諾氟沙星氟哌酸CIPROFLOXACIN環(huán)丙沙星OFLOXACIN氧氟沙星(氟嗪酸),OTHERANTIBIOTICS,VACOMYCIN萬古霉素“TRUMPCARD”LINCOMYXIN林可霉素CLINDAMYCIN克林霉素,抗生素抗菌機(jī)理,1.抑制細(xì)菌細(xì)胞壁的合成,ΒLACTAMSΒ內(nèi)酰胺類)VANCOMYCINCYCLOSERINE(環(huán)絲氨酸),ΒLACTAMSΒ內(nèi)酰胺類),青霉素在細(xì)菌細(xì)胞壁上的作用靶點PENICILLINBINDINGPROTEINPBPSTRANSPEPTIDASE轉(zhuǎn)肽酶TRANSGLYCANASE(轉(zhuǎn)糖基酶),PEPTIDECROSSBRIDGES,,,,(TARGETSITEFORPENICILLIN),VANCOMYCIN,與肽聚糖骨架前體上的D丙氨酸結(jié)合,從而阻止肽聚糖骨架的交聯(lián),,一種D丙氨酸類似物阻斷D丙氨酸參與多肽交聯(lián)橋的合成,CYCLOSERINE(環(huán)絲氨酸),,環(huán)絲氨酸萬古霉素,,,,,2影響細(xì)胞膜的功能,POLYMYCINA、B、C、D、E多粘菌素),AMPHOTERICINB兩性霉素B)BINDINGTOASTEROL(固醇)ANTIFUNGI,3抑制蛋白質(zhì)的合成,AMINOGLYCOSIDES(氨基糖酐類)TETRACYCLINES(四環(huán)素類),與細(xì)菌核糖體30S小亞基結(jié)合,抑制細(xì)菌蛋白質(zhì)的合成,,與細(xì)菌核糖體50S亞基結(jié)合,阻止蛋白質(zhì)合成肽鏈延長,CHLORAMPHENICOL(氯霉素)ERYTHROMYCIN(紅霉素),,4抑制細(xì)菌核酸合成,與細(xì)菌RNA多聚酶結(jié)合,阻止其MRNA轉(zhuǎn)錄結(jié)構(gòu)與對氨苯甲酸PABA類似,可競爭二氫葉酸酶,阻礙二氫葉酸合成,從而影響核酸合成,RIFAMPIN(利福平),磺胺類,細(xì)菌的耐藥性,嚴(yán)重的世界性問題,1928PENICILLINWASDISCOVEREDBYALEXANDERFLEMING1941PENICILLINWASUSEDINTREATINGBACTERIALINFECTIONS1944PENICILLINRESISTANTSTAPHYLOCOCCUS1946141947381966901959BEECHAMANDBRISTOLBROUGHTOUTMETHICILLIN,,,,1961METHICILLINRESISTANTSTAPHYLOCOCCUSAUREUSMRSAWASFIRSTDETECTEDINBRITAIN1987VACONMYCINRESISTANTENTEROBACTERIA(VRE)1997VACONMYCINDEPENDENTENTEROBACTERIA(VDE)2002VACONMYCINRESISTANTSTAPHYLOCOCCUSAUREUSVRSA,,THEMOSTIMPORTANTANTIBIOTICSRESISTANTBACTERIA,STAPHYLOCOCCUS金黃色葡萄球菌TUBERCLEBACILLUS結(jié)核桿菌HAEMOPHILUSINFLUENZA流感嗜血桿菌ENTEROCOCCUS腸球菌PAERUGINOSA銅綠假單胞菌ECOLI大腸桿菌PKLEBSICLLA肺炎克雷伯菌,細(xì)菌耐藥機(jī)理,1產(chǎn)生修飾酶,1)ΒLACTAMASESΒ內(nèi)酰胺酶)破壞Β內(nèi)酰胺環(huán),PENICILLINASE青霉素酶CEPHALOSPORINASE頭孢菌素酶EXTENDEDSPECTRUMΒ–LACTAMASES廣譜Β內(nèi)酰胺酶,2AMINOGLYCOSIDEMODIFIEDENZYMES氨基糖甙類抗生素的鈍化酶▲ACETHLTRANSFERASE乙酰轉(zhuǎn)移酶NH2▲PHOSPHOTRANSFERASE磷酸轉(zhuǎn)移酶OH▲ADENYLTRANSFERASE核苷轉(zhuǎn)移酶OH,3CHLORAMPHENICOLACETYLTRANSFERASECAT氯霉素乙酰轉(zhuǎn)移酶ENCODEDBYPLASMIDCHANGETHESTRUCTUREOFCHLORAMPHENICOLBLOCKINGTHEBINDINGOF50SRIBOSOME,2改變作用靶點或受體靶點,改變細(xì)胞膜上青霉素結(jié)合蛋白PBP2PBP2APBP2A使青霉素結(jié)合量減少,,ALTEREDTARGET(靶點改變),TARGETANTIBIOTICSPBPSΒLACTAMSDNAGYRASEQUINOLONERNAPOLYMERASERIFOMPIN50SSUBUNITERYTHROMYCIN30SSUBUNITSTREPTOMYCIN,,3阻止抗生素進(jìn)入,改變外膜蛋白OMP減少抗生素的滲入主動排出在細(xì)胞膜上合成反向泵系統(tǒng)REVERSEPUMPINGSYSTEM主動派出抗生素,細(xì)菌耐藥性的遺傳基礎(chǔ),細(xì)菌耐藥性的遺傳特點,■INTRINSICRESISTANCE固有耐藥性,天然耐藥性)CHROMOSOMALMUTATION■ACQUIREDRESISTANCE染色體介導(dǎo))獲得性耐藥性PLASMIDMEDIATEDRESISTANCE(質(zhì)粒介導(dǎo)),,,1染色體介導(dǎo)的細(xì)菌耐藥特點,ALTEREDDRUGTARGETS■基因突變DECREASEDPERMEABILITYΒLACTAMASE■生長緩慢FREQUENCYRATE1012107UNABLETOCOMPETEWITHWILDTYPES■臨床相對少見,,2質(zhì)粒/轉(zhuǎn)座子介導(dǎo)的細(xì)菌耐藥特點,■TRANSFORMATION(轉(zhuǎn)化)■TRANSDUCTION(轉(zhuǎn)導(dǎo))■CONJUGATION(接合),有基因轉(zhuǎn)移轉(zhuǎn)移效率高(通常通過接合方式)轉(zhuǎn)移至同種或異種細(xì)菌常涉及多重耐藥性轉(zhuǎn)移導(dǎo)致嚴(yán)重的臨床問題常見轉(zhuǎn)移的耐藥基因有ΒLACTAMASESACETYLTRANSFERRASEADENINEMETHYLASEREVERSEPUMPINGSYSTEMHEAVYMETALRESISTANCE,耐藥質(zhì)粒在細(xì)菌間的傳播,轉(zhuǎn)化轉(zhuǎn)導(dǎo)接合細(xì)菌種屬G()菌葡萄球菌G()菌轉(zhuǎn)移片段極小極小大轉(zhuǎn)移條件受體菌呈噬菌體與宿主性菌毛感受態(tài)有種特異性臨床重要性小小大,,,,,,,3整合子與多重耐藥,可捕獲外源基因同一整合子可攜帶不同耐藥基因盒同一耐藥基因盒可在不同整合子上,細(xì)菌耐藥性的控制策略,合理使用抗生素嚴(yán)格執(zhí)行消毒隔離制度加強藥政管理研發(fā)新型抗生素破壞耐藥基因,THANKYOU,
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