医学专题—人工合成抗菌药PPT.ppt

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1、 Synthetic antimicrobial agents(人工合成人工合成(rn(rn nn h chn h chn)抗菌药抗菌药)Huifang Tang 第一页，共五十四页。Classification of Synthetic antimicrobial agents.Quinolones(喹诺酮类喹诺酮类);.Sulfonamides(磺胺类磺胺类);.Other synthetic antimicrobial agents:Trimethoprim(甲氧苄啶甲氧苄啶)Nitrofurans(硝基硝基(xio j)呋喃类呋喃类),etc.第二页，共五十四页。General fea

2、turesBroad antimicrobial activity and are effective after oral administration for the treatment of a wide variety of infectious disease.Relatively few side effects.Microbial resistance to their action does not develop rapidly.QuinolonesQuinolones 第三页，共五十四页。ChemistryDerived from basic structure of na

3、lidixic acid(萘萘啶酸啶酸)and have substituents at N-1,C-5,C-7,position 8 and a fluorine atom at position 6.Fluorine at position 6 enhances gyrase inhibition and cell penetration.QuinolonesQuinolones 第四页，共五十四页。Chemical structureQuinolones(诺氟沙星诺氟沙星诺氟沙星诺氟沙星)(环丙沙星环丙沙星环丙沙星环丙沙星)(萘啶酸萘啶酸萘啶酸萘啶酸)Quinolones 第五页，共五十

4、四页。Generation Examples1 st(1962-1969)Nalidixic acid,萘啶酸萘啶酸2 nd(1969-1979)Pipemidic acid 吡哌酸吡哌酸Cinoxacin 西诺沙星西诺沙星3 rd(1980-1996)Norfloxacin 诺氟沙星诺氟沙星 Levofloxacin 左氧氟沙星左氧氟沙星 Ciprofloxacin 环丙沙星环丙沙星Ofloxacin 氧氟沙星氧氟沙星sparfloxacin 司帕沙星司帕沙星4 th(1997-)Grepafloxacin 格帕沙星格帕沙星Clinafloxacin 克林沙星克林沙星Gatifloxacin

5、 加替沙星加替沙星Moxifloxacin 莫西沙星莫西沙星ClassificationQuinolones 第六页，共五十四页。Summary of antimicrobial spectrum of quinolones.第七页，共五十四页。Typical therapeutic applications of uoroquinolones.第八页，共五十四页。First-generation agents(1962-1969)Nalidixic acid,萘啶酸萘啶酸 The first generation drug of the quinolone antibioticsThe fi

6、rst generation drug of the quinolone antibiotics Moderate gram-negative activity and minimal systemic Moderate gram-negative activity and minimal systemic distributiondistributionClinical applications Clinical applications Uncomplicated urinary tract infections Uncomplicated urinary tract infections

7、QuinolonesQuinolones 第九页，共五十四页。Second-generation quinolones(1969-1979)Pipemidic acid 吡哌酸吡哌酸 Cinoxacin西诺沙星西诺沙星 Expanded gram-negative activity and atypical pathogen Expanded gram-negative activity and atypical pathogen coverage,but limited gram-positive activity.coverage,but limited gram-positive act

8、ivity.Most active against aerobic gram-negative bacilliMost active against aerobic gram-negative bacilli Ciprofloxacin remains the quinolone most active against Ciprofloxacin remains the quinolone most active against Pseudomonas aeruginosaPseudomonas aeruginosaQuinolonesQuinolones 第十页，共五十四页。Second-g

9、eneration quinolones(1969-1979)Active against gram-positive and gram-negative bacteria,mycobacteria,mycoplasma支原体支原体支原体支原体and and legionella specieslegionella species军团军团军团军团(jntun)(jntun)杆菌属杆菌属杆菌属杆菌属.Longer half-lives due to slow elimination,Longer half-lives due to slow elimination,distribution in

10、to many tissues and body fluids and distribution into many tissues and body fluids and penetration into human cells.penetration into human cells.QuinolonesQuinolones 第十一页，共五十四页。Third-generation quinolones(1980-1996)Norfloxacin 诺氟沙星诺氟沙星，Levofloxacin 左氧氟沙星左氧氟沙星，Ciprofloxacin 环丙沙星环丙沙星，Ofloxacin 氧氟沙星氧氟沙

11、星，Sparfloxacin 司帕沙星司帕沙星Added potency against gram-negative bacteria,Added potency against gram-negative bacteria,anaerobes and mycobacteria.anaerobes and mycobacteria.Retain expanded gram-negative and atypical Retain expanded gram-negative and atypical intracellular activity but have improved gram-i

12、ntracellular activity but have improved gram-positive coveragepositive coverageQuinolonesQuinolones 第十二页，共五十四页。Fourth-generation agents(1997-)Grepafloxacin 格帕沙星，格帕沙星，Clinafloxacin 克林沙星，克林沙星，Gatifloxacin 加替沙星，加替沙星，Moxifloxacin 莫西沙星莫西沙星 Improve gram-positive coverage,maintain gram-Improve gram-positiv

13、e coverage,maintain gram-negative coverage,and gain anaerobic coverage.negative coverage,and gain anaerobic coverage.QuinolonesQuinolones 第十三页，共五十四页。Antimicrobial activity&spectrum(1)Bactericidal and have significant PAE.(1)Bactericidal and have significant PAE.(2)Excellent activity against aerobic

14、gram-negative bacteria,some agents have activity against Pesudomonas.(3)Several newer agents with improved activity against aerobic gram-positive bacteria.QuinolonesQuinolones 第十四页，共五十四页。Antimicrobial activity&spectrum(4)They also are effective against Chlamydia spp.(4)They also are effective agains

15、t Chlamydia spp.（衣原体）（衣原体）（衣原体）（衣原体）,Legionella pneumophila(,Legionella pneumophila(军团菌军团菌军团菌军团菌),anaerobic bacteria,mycobacteria(,anaerobic bacteria,mycobacteria(分枝杆菌分枝杆菌分枝杆菌分枝杆菌).).(5)(5)Some Some agents agents have have limited limited activity activity against against multiple-resistance strains

16、.multiple-resistance strains.（6 6）Bactericidal concentration bacteriostatic Bactericidal concentration bacteriostatic concentrationconcentrationQuinolonesQuinolones 第十五页，共五十四页。Mechanism of actions Topoisomerases:enzymes that control and modify enzymes that control and modify the topological states o

17、f DNA in cells.the topological states of DNA in cells.Topoisomerase ITopoisomerase I，III III catalyse merely the catalyse merely the relaxation of DNArelaxation of DNA Topoisomerase II Topoisomerase II（DNA gyraseDNA gyrase）catalyse the catalyse the supercoiling of DNAsupercoiling of DNATopoisomerase

18、 IVTopoisomerase IV involved in the separation involved in the separation process of the DNA daughter chains after process of the DNA daughter chains after chromosome duplication.chromosome duplication.QuinolonesQuinolones 第十六页，共五十四页。Mechanism of actions The quinolone antibiotics target bacterial Th

19、e quinolone antibiotics target bacterial DNA gyrase(gram-negative bacteria)DNA gyrase(gram-negative bacteria)Topoisomerase IV(gram-positive bacteria).QuinolonesQuinolones 第十七页，共五十四页。Topoisomerase IV:involved in the separation process of Topoisomerase IV:involved in the separation process of the DNA

20、daughter chains after chromosome duplication.the DNA daughter chains after chromosome duplication.unable to catalyse the supercoiling of DNA,merely its unable to catalyse the supercoiling of DNA,merely its relaxation.relaxation.The enzyme comprises two subunits,ParC and ParE.The enzyme comprises two

21、 subunits,ParC and ParE.The ParC protein is homologous to the gyrase A protein,The ParC protein is homologous to the gyrase A protein,while the ParE subunit is homologous to the gyrase B while the ParE subunit is homologous to the gyrase B protein.protein.Mechanism of actionQuinolones 第十八页，共五十四页。Inh

22、ibition of topoisomerase IV Inhibition of topoisomerase IV interferes with interferes with separation of replicated chromosomal DNA into the separation of replicated chromosomal DNA into the respective daughter cells during cell division.respective daughter cells during cell division.Inhibition of D

23、NA gyrase Inhibition of DNA gyrase prevents the relaxation of positively prevents the relaxation of positively supercoiled DNA that is required for normal transcription and supercoiled DNA that is required for normal transcription and replicationreplication.Mechanism of actionQuinolones 第十九页，共五十四页。I

24、ntrinsic resistance is rareWith a frequency of about one in 107109,especially among staphylococci,pseudomonas,and serratia(沙雷氏菌沙雷氏菌).Resistance MechanismQuinolones 第二十页，共五十四页。(1)Mutation of the gyrA genethe gyrA gene that encoded the A subunit polypeptide can confer resistance to these drugs.(2)Muta

25、tion of the gene cfxB and nfxB that encoded the porin decreased permeability of cell membrance.(3)The high expression of(3)The high expression of norA genenorA gene(encoded active pump protein)increased drugs efflex by a active transport protein pump.(4)Plasmid mediated resistance.(4)Plasmid mediate

26、d resistance.Resistance MechanismQuinolones 第二十一页，共五十四页。(1)Well absorbed after oral administration.(2)Distributed widely in body tissue,even in CSF.(3)Excreted mainly in urine.Routes of elimination differ among the Quinolones.ADME of QuinolonesQuinolones 第二十二页，共五十四页。(1)Urinary tract infections.The m

27、ain indication for quinolones The main indication for quinolones In the treatment of uncomplicated and In the treatment of uncomplicated and complicated UTIs,cure rates can exceed 90%complicated UTIs,cure rates can exceed 90%and 80%,respectively.and 80%,respectively.Potent agents to use against Haem

28、ophilus ducreyi(软性软性(ru(ru n xnn xn)下疳嗜血杆菌下疳嗜血杆菌)and penicillin-sensitive and penicillin-resistant Neisseria gonorrhoeae淋淋(病双病双)球菌球菌.Clinical UsesQuinolones 第二十三页，共五十四页。(2)GI and abdominal infections.Excellent in vitro activity against many enteric Excellent in vitro activity against many enteric pa

29、thogens,including Escherichia colipathogens,including Escherichia coli大肠杆菌大肠杆菌大肠杆菌大肠杆菌,AeromonasAeromonas气单胞菌属气单胞菌属气单胞菌属气单胞菌属,Shigella,Shigella志贺志贺(氏氏)杆菌杆菌(gnjn),SalmonellaSalmonella沙门氏菌沙门氏菌,Campylobacter弯曲杆菌属弯曲杆菌属,VibrioVibrio弧菌属弧菌属,and Yersinia species,and Yersinia species耶尔森菌耶尔森菌耶尔森菌耶尔森菌 Furtherm

30、ore,quinolone drug concentrations in Furthermore,quinolone drug concentrations in feces are exceedingly high.feces are exceedingly high.Clinical UsesQuinolones 第二十四页，共五十四页。(3)Respiratory tract infections.Have inferior activity against streptococciHave inferior activity against streptococci链球菌链球菌链球菌链

31、球菌and should and should not be used as primary therapy for common upper not be used as primary therapy for common upper respiratory tract infections.respiratory tract infections.Alternatives for treatment of acute exacerbation of chronic Alternatives for treatment of acute exacerbation of chronic br

32、onchitis in patients with obstructive pulmonary disease bronchitis in patients with obstructive pulmonary disease who are intolerant of or have developed resistance to first-who are intolerant of or have developed resistance to first-line antibiotics.line antibiotics.antibiotics with activity agains

33、t Streptococcus antibiotics with activity against Streptococcus pneumoniae,Haemophilus influenzaepneumoniae,Haemophilus influenzae流感流感流感流感(嗜血嗜血嗜血嗜血(sh xu)(sh xu)杆菌杆菌杆菌杆菌,and Moraxella catarrhalisand Moraxella catarrhalis粘膜炎莫拉菌粘膜炎莫拉菌粘膜炎莫拉菌粘膜炎莫拉菌.(4)Other infections：Bone,joint and soft tissue infectio

34、ns.Clinical UsesQuinolones 第二十五页，共五十四页。(1)Gastrointestinal effects.(1)Gastrointestinal effects.The most common reactions The most common reactions(2)CNS side effects.(2)CNS side effects.Penetrate BBBPenetrate BBB GABA GABA(3)Allergic reaction.(3)Allergic reaction.Skin rashses,itchs,angioneuroedema,e

35、tc.Skin rashses,itchs,angioneuroedema,etc.PhotosensitivityPhotosensitivity(4)other effects.(4)other effects.Cardiac toxicityCardiac toxicity：Q-T interval Q-T interval Liver and renal injuryLiver and renal injuryAdverse reactionsQuinolones 第二十六页，共五十四页。(4)other effects.Muscle skeletal system Amyasthen

36、ia 肌无力肌无力,myosalgia肌痛肌痛,joint pain and inflammationIncrease intracranial pressure in infantsAdverse reactionsQuinolones 第二十七页，共五十四页。Pipemidic acid (吡哌酸吡哌酸)Norfloxacin (诺氟沙星诺氟沙星)Ciprofloxacin (环丙杀星环丙杀星)Ofloxacin（氧氟沙星）（氧氟沙星）Levofloxacin（左氧氟沙星）（左氧氟沙星）Lomefloxacin（洛美沙星）（洛美沙星）Fleroxacin（氟罗沙星）（氟罗沙星）Sparfl

37、oxacin（司帕沙星）（司帕沙星）Quinolones agentsQuinolones 第二十八页，共五十四页。PharmacokineticPharmacokinetic PropertiesProperties ofof FluoroquinolonesFluoroquinolonesQuinolones 第二十九页，共五十四页。盐酸(yn sun)安妥沙星-我国第一个具有自主知识产权的沙星类抗菌药 盐酸安妥沙星与细菌作用2到4小时，即可杀灭99%以上细菌。在沙星类药物安全性的重要指标光毒性方面，它的毒性明显低于现有主要产品洛美沙星、司帕沙星、氟罗沙星、环丙沙星。盐酸安妥沙星具有优异的

38、药物代谢性质，与最新的第四代沙星类药物相比，它的口服剂量最低，每天只需服用1次，属长效抗菌药物。盐酸安妥沙星治疗呼吸道、泌尿道、皮肤软组织等三大系统细菌感染性疾病，疗效(lioxio)确切而不良反应少，总有效率超过95%。第三十页，共五十四页。喹诺酮类研究(ynji)两大动向 继续研发第四代氟喹诺酮近年上市(shng sh)的:吉米沙星(gemifloxacin),巴洛沙星目前正在研发中的:西他沙星(sitafloxacin),奥鲁沙星(olamufloxacin)。注意研究结构变幅更大的喹诺酮近年上市的帕珠沙星(pazufloxacin)、鲁利沙星(prulifloxacin)非氟喹诺酮格林

39、沙星(garenoxacin)第三十一页，共五十四页。Sulfonamides第三十二页，共五十四页。SulfonamidesSulfonamides 第三十三页，共五十四页。(1)Sulfonamides have a wide range of antimicrobial activity.G+,G-bacteria,Nocardia 诺卡菌属诺卡菌属,Bedsonia trachomatis沙眼沙眼(shyn)(shyn)衣原体衣原体,etc.Enteric bacteria etc.less effectiveRicketts organism(2)Sulfonamides exert

40、 only bacteriostatic effect.Antimicrobial activitySulfonamides 第三十四页，共五十四页。Structural analogs and competitive antagonists of para-aminobenzoic acid(对氨基对氨基(nj)(nj)苯甲酸苯甲酸 PABA)Prevent normal bacterial utilization of PABA for the synthesis of folic acid.Mechanism of actionSulfonamides 第三十五页，共五十四页。Mecha

41、nism of actionSulfonamides 第三十六页，共五十四页。Originate by random mutation and selection or by transfer of resistance by plasmaides.Such resistance usually is persistent and irreversible.Mechanism of ResistanceSulfonamides 第三十七页，共五十四页。The resistance characterized by:(1)A lower affinity for sulfonamides by

42、the dihydropteroate synthase(2)Decreased cell permeability or active efflux of the drug(3)An alternative pathway to synthesis the essential metabolites(4)An increased production of essential metaboltesMechanism of ResistanceSulfonamides 第三十八页，共五十四页。(1)Oral absorbable agentsShort-acting agentsShort-a

43、cting agentsMedium-acting agentsLong-acting agentsLong-acting agents(2)Oral nonabsorbable agents(3)Topical agents.(3)Topical agents.(4)Combination agents.ClassificationSulfonamides 第三十九页，共五十四页。(1)(1)systemic infections.systemic infections.cerebral meningitis cerebral meningitis Tympanitis Tympanitis

44、 中耳炎中耳炎中耳炎中耳炎 Uncomplicated urinary tract infectionsUncomplicated urinary tract infections Combined with TMP in treating complicated urinary Combined with TMP in treating complicated urinary tract infections,respiratory infections,GI infectionstract infections,respiratory infections,GI infections(2)

45、intestinal infections.(2)intestinal infections.Sulfasalazine Sulfasalazine 柳氮磺吡啶柳氮磺吡啶柳氮磺吡啶柳氮磺吡啶(b(b dng)dng)(3)infections of burn and wound.(3)infections of burn and wound.Sulfadiazine sliver(Sulfadiazine sliver(磺胺嘧啶银磺胺嘧啶银磺胺嘧啶银磺胺嘧啶银)Clinical usesSulfonamides 第四十页，共五十四页。(1)Urinary tract disturbances(

46、1)Urinary tract disturbances(2)Hypersensitivity reaction(2)Hypersensitivity reaction(3)Hematopoietic system disturbances(3)Hematopoietic system disturbances(4)Kernicterus 脑核黄疸脑核黄疸(hungd(hungd n)n)caused by bilirubincaused by bilirubin胆红素胆红素胆红素胆红素 replacement replacement(5)Hepatitis(6)GI disturbances

47、 Adverse reactionsSulfonamides 第四十一页，共五十四页。(1)Approximately 70%-100%of an oral dose is(1)Approximately 70%-100%of an oral dose is absorbed.absorbed.(2)Sulfonamides are distributed throughout all(2)Sulfonamides are distributed throughout all tissues of the body,even in CSF tissues of the body,even in

48、 CSF Sulfadiazine磺胺磺胺(hun(hun n)n)嘧啶嘧啶and sulfisoxazole磺磺胺胺(hun(hun n)n)异恶唑异恶唑,may be effective in meningeal infections.(3)Sulfonamides readily pass though the(3)Sulfonamides readily pass though the placenta.placenta.ADME of sulfonamidesSulfonamides 第四十二页，共五十四页。(4)Sulfonamides are metabolized in the

49、 liver by acetylation.(5)Sulfonamides eliminated mainly in the urine as the unchanged drug and metabolic product.In acid urine,the eliminated are insoluble and may precipitate,thus induced renal disturbance.ADME of sulfonamidesSulfonamides 第四十三页，共五十四页。Increase the effects of tolbutamide甲苯甲苯(ji(ji bn

50、)bn)磺丁脲磺丁脲,warfarin,trexan甲氨甲氨喋呤喋呤The reason is:all sulfonamides are bound in varying degree to plasma protein.Drugs interactionsSulfonamides 第四十四页，共五十四页。(1)Oral absorbable agentsShort-acting agentsSulfafurazole(SIZ,菌得清菌得清)Sulfadimidine,(SN2,磺胺二甲磺胺二甲(r ji(r ji)嘧啶嘧啶)Medium-acting agentsSulfadiazine(S