MLS类抗生素及细菌耐药性

1、1会计学MLS类抗生素及细菌耐药性类抗生素及细菌耐药性OH3COHCH3OCH3OOOHCH3OH3COHH3CCH3OOHCH3OCH3OHOErythromycin ANH3CCH3CH3CH32OOHCH3OOHH3COOH3COHOCH3OOOHCH3OOCH3CH3NH3CCH3Leucomycin A1HCOCH3OOHCH3OOH3COOH3COHOCH3OOOHCH3OCH3ONCH3HCOOCH3Midecamycin A1H3CCH3OCH3ORH3COH3COCHOONCH3Spiramycin IR = HSpiramycin IICH3CH3R = COCH3Spir

2、amycin IIIOOCH3NCH3H3COR = COCH2CH3HOOOHOHCH3CH3OOH3COHOOH3CH3CH3COCH3CH3OOCH3OCH3OHONH3CCH3CH3OHO竹桃霉素OOH3COOHH3CCH3CH3HCOONH3CCH3HOCH3OOHCH3OHCH3OOOOOCH3OCH3HOH3C泰乐菌素 H3COOH3COHOOCH3CH3ORCH3OHNH3CCH3OHOOR =OOCH3OCH3CH3CH3OHCO交沙霉素 NOCH3H3CNHCHHOCH3OOHCHSCH3OHHO林可霉素类抗生素的化学结构 链阳性菌素A链阳性菌素B大环内酯类抗生素与50S核

3、糖体亚单位可逆性地结合，阻断肽链的延伸 MLSB类抗生素对50S核糖体亚基结合位点的拓模式 MLS类抗生素肽酰基转移酶结构域 III链阳性菌素B类 14元大环内酯类16元大环内酯类 链阳性菌素A类 林可类 VS ERY LEU/SPM VM LIN 组分组分MIC(ml/L)MIC(ml/L)CFUCFU蛋白质合成蛋白质合成抑制模式抑制模式A A或或B B100100不变不变可逆可逆A+BA+B1 1降低降低1010-2 -2 1010-3-3不可逆不可逆耐药机制耐药机制基因基因对各种对各种MLS类抗生素产生耐药性类抗生素产生耐药性aEryOleMacLinCliSgBSgASg靶位修饰靶位修

4、饰ermbermcRRS/RRSRSRSRSRSSSs药物钝化药物钝化linAlsasaa-sbhSSSSSSSSSRIS/IsIS/ISSRSRRSIR主动转运主动转运epAdmsrARRRRSSSSSSSReSSSND外排机制细菌名称细菌名称被钝化的被钝化的抗生素抗生素钝化酶名称钝化酶名称基因定位基因定位基因基因名称名称金黄色葡萄球菌金黄色葡萄球菌SASBLLSA O-酰基转移酶酰基转移酶SB 水解酶水解酶ND -L O-核苷酰转移酶核苷酰转移酶 pIP524pIP524NDpIP856saasbhLinA人葡萄球菌人葡萄球菌MND pIP860溶血葡萄球菌溶血葡萄球菌L-L O-核苷酰转

5、移酶核苷酰转移酶pIP855LinA乳房链球菌乳房链球菌L-L O-核苷酰转移酶核苷酰转移酶NDLinA屎链球菌屎链球菌SANDpIP815乳酸杆菌属乳酸杆菌属MSAML MSMLSNDNDND产气荚膜梭状产气荚膜梭状芽孢杆菌芽孢杆菌SNDND 链霉菌链霉菌MLLND3-L O-磷酸转移酶磷酸转移酶3-L O-核苷酰转移酶核苷酰转移酶NDNDND假单孢菌假单孢菌MNDND大肠艾希氏菌大肠艾希氏菌MMM红霉素红霉素I型酯酶型酯酶红霉素红霉素II型酯酶型酯酶大环内酯大环内酯2-磷酸转移酶磷酸转移酶pIP1100pIP1527NDereAereBONCH3OHH3CCH312345OCH3OHCH3

6、OCH312345R1desosamineOH3CHOOCH2OOCH3HOCH3CH3OHOCH3R1CH3R2CH3H2OOHOHOH3COHCH3CH3HOCH3CH3OR1OR2CH3OHOC123456789101112131415123456789101112131415R2cladinose碱基发生改变的位点及种类碱基发生改变的位点及种类微生物名称微生物名称对抗生素敏感性的影响对抗生素敏感性的影响C2611UC2611UC2611GC2611GC2611G大肠艾希氏菌大肠艾希氏菌Chlamydomonas reinhardtiiChlamydomonas reinhardtii酿

7、酒酵母酿酒酵母Chlamydomonas moewuseiChlamydomonas reinhardtiiEryr Linr SgbrEryr ClnrEryr SpirEryrEryr ClnrG2032AG2032AG2032UG2032CNicotiana pltonbaginafoliaNicotiana pltonbaginafolia大肠艾希氏菌大肠艾希氏菌大肠艾希氏菌大肠艾希氏菌大肠艾希氏菌大肠艾希氏菌LinrEryhs Clnr CamrEryhs Clns CamrEryhs Clns CamsG2057AG2057AChlamydomonas reinhardtiiChl

8、amydomonas reinhardtii大肠艾希氏菌大肠艾希氏菌Eryr Lins ClnsEryr CamrA2058GA2058GA2058GA2058GA2058GA2058CA2058UA2058UChlamydomonas reinhardtiiChlamydomonas reinhardtii大肠艾希氏菌大肠艾希氏菌Nicotiana pltonbaginafoliaNicotiana pltonbaginafolia酿酒酵母酿酒酵母intracellulare 分支杆菌分支杆菌intracellulare 分支杆菌分支杆菌大肠艾希氏菌大肠艾希氏菌intracellulare

9、分支杆菌分支杆菌Eryr Linr CamrEryrLinrEryrClarClarEryrClarA2059GNicotiana Nicotiana pltonbaginafoliapltonbaginafoliaLinrA2062Chalobiton嗜盐菌嗜盐菌CamrG2447CG2447AHonia sapiensHonia sapiens酿酒酵母酿酒酵母AnirCamrA2451UMusmucseulusMusmucseulusCamrC2452AC2452AC2452UC2452UC2452UHonia sapiensHonia sapiensMusmucseulusSulfolo

10、bus acidoculdariusTetrahymena thermophilaCamrCamrCamrCamr Carr CelrAnirA2453CHalobiton嗜盐菌嗜盐菌AnirA2503CA2503C大肠艾希氏菌大肠艾希氏菌酿酒酵母酿酒酵母CamrCamrU2504CU2504AU2503CHonia sapiensHonia sapiensMusmucseulusMusmucseulusCamrCamrCamr基因基因微生物来源微生物来源ermA金黄色葡萄球菌金黄色葡萄球菌emAM血链球菌血链球菌ermB金黄色葡萄球菌金黄色葡萄球菌ermBC大肠艾希氏菌大肠艾希氏菌ermB类

11、类粪链球菌粪链球菌ermC金黄色葡萄球菌金黄色葡萄球菌ermCD白喉棒壮杆菌白喉棒壮杆菌ermD地衣型芽孢杆菌地衣型芽孢杆菌ermE红霉糖多孢菌红霉糖多孢菌ermF脆弱拟杆菌，脆弱拟杆菌，ermFS脆弱拟杆菌脆弱拟杆菌ermFU脆弱拟杆菌脆弱拟杆菌ermG芽孢杆菌芽孢杆菌ermGTreuteri乳酸杆菌乳酸杆菌ermIM枯草杆菌枯草杆菌ermJ炭疽杆菌炭疽杆菌ermK地衣型芽孢杆菌地衣型芽孢杆菌ermM表皮葡萄球菌表皮葡萄球菌ermP产气荚膜梭状芽孢杆菌产气荚膜梭状芽孢杆菌ermQ产气荚膜梭状芽孢杆菌产气荚膜梭状芽孢杆菌ermR(ermAAR)藤黄节杆菌藤黄节杆菌ermSF费氏链霉菌费氏链霉菌

12、ermTR酿脓链球菌酿脓链球菌ermZ艰难梭菌艰难梭菌不同微生物来源的甲基化酶的基因 NNNNNCH2OHHOOO POOHOOSOHOHNH2CH312345CONHCH2NH2CH2CCH3CHHCCH3RAMPR=OH林可霉素R=CL克林霉素OOOOOHOOHOH16891112EM-AOOHOMeONMe2HO423*8-F(氟红霉素)8-OH6-O-甲基(克拉红霉素)*3-C=O 4-OSO2-R 4=O,4=NOH,4-NH-R*4-H, *4-O-R, *4-OCO-NH24-OCO-R 9-氨基乙叉(地红霉素) 9=NOH, 9=N-NH2, 9-NH2 9-NH-Ts, *9

13、-NRR, *9=NO-R *9-SH, *9-deoxo*9-deoxo-aza-homo (阿齐红霉素)9=NO-MEM(罗红霉素)*translactonization (产物)11,12-acetal11,12-carbonate (Davercin) *11-O-R, *11=O *11, 12-carbamate*9, 11-or 11,12-methylene *11-NH2-6,9-epopxy *12-O-R *12-carbamate *14-OH *21-OH *21-NMe2*6-OCONH2 *6-OAc, *6-deoxy2-propionate 3-lauryl

14、sulfate2-ethyl succinate *2-acetate 3-stearate (Acistrate) *2-O-TMS3-stearate 2-NMe2 3-R3-lactobionate*3-cysteine salt (Stinoprate)3-NMe-R, NMe2R-X(*Motilide, EM 523)4-OH后于克拉红霉素CH3OOH3CNCH3CH3H3COHCH3OHH3COHOOOCH3ONCH3H3CCH3HOOOCH3OOHCH3H3CONHH3CH3CCH3OOCH3OOHCH3OHH3CH3CONCH3H3CCH3OHOOOOCH3OHCH3CH3O

15、H3CO 罗红霉素 地红霉素OHH3COH3COHOCH3CH3H3CCH3OCH3OOOH3COOCH3CH3OHCH3OHONCH3H3CCH3克拉红霉素 氟红霉素NOH3COHOHH3COCH3CH3H3CCH3OHCH3H3COCH3NH3CCH3OHOOOCH3OCH3OHCH3阿齐红霉素OOH3COH3COHOHCH3HCOONCH3H3CCH3HOOOOOCH3CH3OCH3OOCH3罗他霉素 OOCH3OOH3COOH3COHOCH3OOOCH3OCH3ONCH3HCOOCH3H3CCH3CH3OCH3O乙酰麦迪霉素品名品名化学结构化学结构抗菌谱抗菌谱临床药理临床药理罗红霉素罗

16、红霉素(RXM)(RXM)1414元环元环C-9C-9肟衍生物肟衍生物与与EMEM近似近似血峰浓度高，消除半衰期血峰浓度高，消除半衰期12 h12 h，组织渗透性好，组织渗透性好地红霉素地红霉素(DRM)(DRM)1414元环元环C-9C-9，1111恶嗪恶嗪衍生物衍生物与与EMEM近似近似组织浓度高且持久，血药组织浓度高且持久，血药浓度低但半衰期长浓度低但半衰期长克拉红霉素克拉红霉素(CAM)(CAM)1414元环元环6-O-6-O-甲基衍生甲基衍生物物抗革兰阴性菌及军团抗革兰阴性菌及军团菌菌血药浓度与组织浓度均高血药浓度与组织浓度均高氟红霉素氟红霉素(FUM)(FUM)1414元环元环8-

17、8-氟基衍生物氟基衍生物与与EMEM近似近似组织浓度较高，血中半衰组织浓度较高，血中半衰期期8h8h阿齐红霉素阿齐红霉素(AZM)(AZM)1515元环元环C-9C-9”叔胺衍叔胺衍生物生物抗革兰阴性菌抗革兰阴性菌组织浓度明显高于血药浓组织浓度明显高于血药浓度且持久，胞内浓度度且持久，胞内浓度高高罗他霉素罗他霉素(RKM)(RKM)1616元环元环3 3”- -酯衍生物酯衍生物抗军团菌、支原体和抗军团菌、支原体和部分耐部分耐EMEM葡球菌葡球菌组织浓度高于血药浓度，组织浓度高于血药浓度，胞内浓度高胞内浓度高米欧卡霉素（米欧卡霉素（MOMMOM，乙酰麦迪霉素）乙酰麦迪霉素）1616元环元环3 3

18、”- -酯衍生物酯衍生物与与RKMRKM近似近似血药浓度及半衰期均优于血药浓度及半衰期均优于母体化合物麦迪霉素母体化合物麦迪霉素新大环内酯抗生素特征比较 抗菌药物名称抗菌药物名称试验浓度范围试验浓度范围（g/mlg/ml）MICMIC（g/mlg/ml）范围范围50%50%90%90%二甲胺四环素二甲胺四环素0.00780.00788 80.0620.0620.250.250.1250.1250.250.25红霉素红霉素0.000240.000240.250.250.00190.00190.00780.00780.00390.00390.00780.0078甲红霉素甲红霉素0.000240.0

19、00240.250.250.000480.000480.00390.00390.00190.00190.00190.0019罗红霉素罗红霉素0.000240.000240.250.250.00190.00190.00780.00780.00390.00390.00780.0078阿齐霉素阿齐霉素0.000030.000030.0310.0310.000060.000060.000480.000480.000240.000240.000480.00048交沙霉素交沙霉素0.000240.000240.250.250.00190.00190.03130.03130.00780.00780.0156

20、0.0156左氧氟沙星左氧氟沙星0.00780.00788 80.1250.1250.50.50.250.250.250.25泰莱霉素泰莱霉素0.000030.000030.0310.0310.000240.000240.00190.00190.000970.000970.000970.00097泰利霉素和其它一些抗菌药物的抗肺炎支原体活性比较泰利霉素的化学结构菌菌 株株MICMIC（g/mlg/ml）泰利霉素泰利霉素红霉素红霉素康氏立克次氏体康氏立克次氏体( (Richettsia conoriiRichettsia conorii) ) MoroccanMoroccan (ATC VR (

21、ATC VR14)14)0.50.58 8康氏立克次氏体康氏立克次氏体( (Richettsia conoriiRichettsia conorii) ) serotype serotype Israeli Israeli0.50.58 8立氏立克次氏体立氏立克次氏体( (Richettsi rickettsiiRichettsi rickettsii) ) Sheila SmithSheila Smith (ATCC VR (ATCC VR149)149)0.5-10.5-18 8Rickettsia africaeRickettsia africae0.50.58 8斑疹伤寒立克次氏体斑疹

22、伤寒立克次氏体( (Rickettsia typhiRickettsia typhi) ) WilnmingtonWilnmington (ATCC VR (ATCC VR144)144)0.50.50.5-10.5-1普氏立克次氏体普氏立克次氏体(Rickettsia prowazekii) Breinl (ATCC VR(Rickettsia prowazekii) Breinl (ATCC VR142)142)0.50.50.125-0.250.125-0.25汉氏巴尔通氏体汉氏巴尔通氏体( (Bartonella henselaeBartonella henselae) ) Houst

23、onHouston 1 (ATCC 49882) 1 (ATCC 49882)和和UR.LL.E.9UR.LL.E.90.0030.0030.06-0.250.06-0.25五日热巴尔通氏体五日热巴尔通氏体( (Bartonella quinanaBartonella quinana) ) OklahomaOklahoma (ATCC49793) (ATCC49793)和和UR.P.IE.H2UR.P.IE.H20.0060.0060.006-0.120.006-0.12杆状巴尔通氏体杆状巴尔通氏体(Bartonella baciliiformis)(Bartonella baciliifor

24、mis)KC583(ATCC35685)KC584(ATCC35686)KC583(ATCC35685)KC584(ATCC35686)0.0150.0150.060.06Acochaca 812Acochaca 812，和，和Moazon 269 Moazon 269 伯氏考克氏体伯氏考克氏体Nine MileNine Mile1 18 8Q212Q2121 18 8PriscillaPriscilla1 18 8和红霉素对立克次氏体、巴尔通氏体和伯氏考克氏体的MICs比较Cethromycin的化学结构抗菌药物抗菌药物MICMIC（g/mlg/ml）MBCMBC（g/mlg/ml）90%90%范围范围50%50%90%90%范围范围Cethromycin0.008-0.0150.0150.0150.008-0.0150.015泰莱霉素泰莱霉素0.015-0.250.030.060.015-0.