人工合成抗菌药PPT

1、 Synthetic antimicrobial agents(人工合成抗菌药)Huifang Tang Classification of Synthetic antimicrobial agents . Quinolones(喹诺酮类); . Sulfonamides(磺胺类); . Other synthetic antimicrobial agents: Trimethoprim (甲氧苄啶) Nitrofurans (硝基呋喃类), etc.General featuresBroad antimicrobial activity and are effective after ora

2、l 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 ChemistryDerived from basic structure of nalidixic acid (萘啶酸)and have substituents at N-1, C-5, C-7, position 8

3、and a fluorine atom at position 6. Fluorine at position 6 enhances gyrase inhibition and cell penetration. QuinolonesQuinolones Chemical structureQuinolones(诺氟沙星)(环丙沙星)(萘啶酸)Quinolones Generation Examples1 st (1962-1969) Nalidixic acid, 萘啶酸2 nd (1969-1979) Pipemidic acid 吡哌酸Cinoxacin 西诺沙星3 rd (1980-1

4、996) Norfloxacin 诺氟沙星 Levofloxacin 左氧氟沙星 Ciprofloxacin 环丙沙星Ofloxacin 氧氟沙星sparfloxacin 司帕沙星4 th (1997-) Grepafloxacin 格帕沙星Clinafloxacin 克林沙星Gatifloxacin 加替沙星Moxifloxacin 莫西沙星ClassificationQuinolones Summary of antimicrobial spectrum of quinolones. Typical therapeutic applications of uoroquinolones.Fi

5、rst-generation agents(1962-1969) Nalidixic acid, 萘啶酸The first generation drug of the quinolone antibiotics Moderate gram-negative activity and minimal systemic distributionClinical applications Uncomplicated urinary tract infectionsQuinolonesQuinolones Second-generation quinolones (1969-1979) Pipemi

6、dic acid 吡哌酸 Cinoxacin西诺沙星Expanded gram-negative activity and atypical pathogen coverage, but limited gram-positive activity. Most active against aerobic gram-negative bacilliCiprofloxacin remains the quinolone most active against Pseudomonas aeruginosaQuinolonesQuinolones Second-generation quinolon

7、es (1969-1979) Active against gram-positive and gram-negative bacteria, mycobacteria, mycoplasma支原体and legionella species军团杆菌属. Longer half-lives due to slow elimination, distribution into many tissues and body fluids and penetration into human cells. QuinolonesQuinolones Third-generation quinolones

8、 (1980-1996) Norfloxacin 诺氟沙星， Levofloxacin 左氧氟沙星， Ciprofloxacin 环丙沙星， Ofloxacin 氧氟沙星， Sparfloxacin 司帕沙星Added potency against gram-negative bacteria, anaerobes and mycobacteria. Retain expanded gram-negative and atypical intracellular activity but have improved gram-positive coverageQuinolonesQuinol

9、ones Fourth-generation agents (1997- ) Grepafloxacin 格帕沙星，Clinafloxacin 克林沙星，Gatifloxacin 加替沙星，Moxifloxacin 莫西沙星Improve gram-positive coverage, maintain gram-negative coverage, and gain anaerobic coverage.QuinolonesQuinolones Antimicrobial activity & spectrum(1) Bactericidal and have significant PAE

10、. (2)Excellent activity against aerobic gram-negative bacteria, some agents have activity against Pesudomonas. (3) Several newer agents with improved activity against aerobic gram-positive bacteria.QuinolonesQuinolones Antimicrobial activity & spectrum(4) They also are effective against Chlamydia sp

11、p.（衣原体）, Legionella pneumophila(军团菌) ,anaerobic bacteria, mycobacteria(分枝杆菌).(5) Some agents have limited activity against multiple-resistance strains.（6）Bactericidal concentration bacteriostatic concentrationQuinolonesQuinolones Mechanism of actions Topoisomerases : enzymes that control and modify

12、the topological states of DNA in cells. Topoisomerase I， III catalyse merely the relaxation of DNATopoisomerase II （DNA gyrase） catalyse the supercoiling of DNATopoisomerase IV involved in the separation process of the DNA daughter chains after chromosome duplication.QuinolonesQuinolones Mechanism o

13、f actions The quinolone antibiotics target bacterial DNA gyrase (gram-negative bacteria) Topoisomerase IV (gram- positive bacteria).QuinolonesQuinolones Topoisomerase IV : involved in the separation process of the DNA daughter chains after chromosome duplication.unable to catalyse the supercoiling o

14、f DNA, merely its relaxation. The enzyme comprises two subunits, ParC and ParE.The ParC protein is homologous to the gyrase A protein, while the ParE subunit is homologous to the gyrase B protein.Mechanism of actionQuinolones Inhibition of topoisomerase IV interferes with separation of replicated ch

15、romosomal DNA into the respective daughter cells during cell division.Inhibition of DNA gyrase prevents the relaxation of positively supercoiled DNA that is required for normal transcription and replication. Mechanism of actionQuinolones Intrinsic resistance is rareWith a frequency of about one in 1

16、07109, especially among staphylococci, pseudomonas, and serratia(沙雷氏菌).Resistance MechanismQuinolones (1) Mutation of the gyrA gene that encoded the A subunit polypeptide can confer resistance to these drugs.(2) Mutation of the gene cfxB and nfxB that encoded the porin decreased permeability of cell

17、 membrance. (3) The high expression of norA gene (encoded active pump protein) increased drugs efflex by a active transport protein pump.(4) Plasmid mediated resistance.Resistance MechanismQuinolones (1) Well absorbed after oral administration.(2) Distributed widely in body tissue, even in CSF.(3) E

18、xcreted mainly in urine. Routes of elimination differ among the Quinolones. ADME of QuinolonesQuinolones Urinary tract infections.The main indication for quinolones In the treatment of uncomplicated and complicated UTIs, cure rates can exceed 90% and 80%, respectively.Potent agents to use against Ha

19、emophilus ducreyi (软性下疳嗜血杆菌) and penicillin-sensitive and penicillin-resistant Neisseria gonorrhoeae淋(病双)球菌. Clinical UsesQuinolones (2) GI and abdominal infections.Excellent in vitro activity against many enteric pathogens, including Escherichia coli大肠杆菌, Aeromonas气单胞菌属, Shigella志贺(氏)杆菌, Salmonella

20、沙门氏菌, Campylobacter弯曲杆菌属, Vibrio弧菌属, and Yersinia species耶尔森菌Furthermore, quinolone drug concentrations in feces are exceedingly high. Clinical UsesQuinolones (3) Respiratory tract infections.Have inferior activity against streptococci链球菌and should not be used as primary therapy for common upper res

21、piratory tract infections. Alternatives for treatment of acute exacerbation of chronic bronchitis in patients with obstructive pulmonary disease who are intolerant of or have developed resistance to first-line antibiotics. antibiotics with activity against Streptococcus pneumoniae, Haemophilus influ

22、enzae流感(嗜血)杆菌, and Moraxella catarrhalis粘膜炎莫拉菌. (4) Other infections： Bone, joint and soft tissue infections.Clinical UsesQuinolones (1)Gastrointestinal effects.The most common reactions (2)CNS side effects.Penetrate BBB GABA(3)Allergic reaction.Skin rashses, itchs, angioneuroedema , etc.Photosensit

23、ivity(4)other effects.Cardiac toxicity： Q-T intervalLiver and renal injuryAdverse reactionsQuinolones (4)other effects.Muscle skeletal system Amyasthenia 肌无力, myosalgia肌痛, joint pain and inflammationIncrease intracranial pressure in infantsAdverse reactionsQuinolones Pipemidic acid (吡哌酸)Norfloxacin

24、(诺氟沙星)Ciprofloxacin (环丙杀星)Ofloxacin（氧氟沙星）Levofloxacin（左氧氟沙星）Lomefloxacin（洛美沙星）Fleroxacin（氟罗沙星）Sparfloxacin（司帕沙星）Quinolones agentsQuinolones Pharmacokinetic Properties of FluoroquinolonesQuinolones 盐酸安妥沙星-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

25、沙星、环丙沙星。盐酸安妥沙星具有优异的药物代谢性质，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，疗效确切而不良反应少，总有效率超过95%。喹诺酮类研究两大动向 继续研发第四代氟喹诺酮近年上市的: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 )非氟喹诺酮格林沙星(garen

26、oxacin ) SulfonamidesSulfonamidesSulfonamides (1) Sulfonamides have a wide range of antimicrobial activity.G+,G- bacteria, Nocardia 诺卡菌属, Bedsonia trachomatis沙眼衣原体, etc.Enteric bacteria etc. less effectiveRicketts organism (2) Sulfonamides exert only bacteriostatic effect.Antimicrobial activitySulfo

27、namides Structural analogs and competitive antagonists of para-aminobenzoic acid (对氨基苯甲酸 PABA) Prevent normal bacterial utilization of PABA for the synthesis of folic acid. Mechanism of actionSulfonamides Mechanism of actionSulfonamides Originate by random mutation and selection or by transfer of re

28、sistance by plasmaides. Such resistance usually is persistent and irreversible. Mechanism of ResistanceSulfonamides The resistance characterized by:(1)A lower affinity for sulfonamides by the dihydropteroate synthase(2)Decreased cell permeability or active efflux of the drug(3)An alternative pathway

29、 to synthesis the essential metabolites(4)An increased production of essential metaboltesMechanism of ResistanceSulfonamides (1) Oral absorbable agentsShort-acting agentsMedium-acting agentsLong-acting agents(2) Oral nonabsorbable agents (3) Topical agents.(4) Combination agents. ClassificationSulfo

30、namides systemic infections.cerebral meningitis Tympanitis 中耳炎Uncomplicated urinary tract infectionsCombined with TMP in treating complicated urinary tract infections,respiratory infections,GI infections(2) intestinal infections.Sulfasalazine 柳氮磺吡啶(3) infections of burn and wound.Sulfadiazine sliver

31、(磺胺嘧啶银)Clinical usesSulfonamides (1)Urinary tract disturbances(2)Hypersensitivity reaction(3)Hematopoietic system disturbances(4)Kernicterus 脑核黄疸caused by bilirubin胆红素 replacement(5)Hepatitis(6)GI disturbances Adverse reactionsSulfonamides (1) Approximately 70%-100% of an oral dose is absorbed.(2) S

32、ulfonamides are distributed throughout all tissues of the body, even in CSF Sulfadiazine磺胺嘧啶and sulfisoxazole磺胺异恶唑, may be effective in meningeal infections .(3) Sulfonamides readily pass though the placenta.ADME of sulfonamidesSulfonamides (4) Sulfonamides are metabolized in the liver by acetylatio

33、n. (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 Increase the effects of tolbutamide甲苯磺丁脲, warfarin , trexan甲氨喋呤The reason

34、is: all sulfonamides are bound in varying degree to plasma protein.Drugs interactionsSulfonamides (1) Oral absorbable agentsShort-acting agentsSulfafurazole(SIZ,菌得清)Sulfadimidine,(SN2,磺胺二甲嘧啶)Medium-acting agentsSulfadiazine(SD,磺胺嘧啶)Sulfamethoxazole(SMZ,新诺明)Long-acting agentsSulfamonomethoxine(SMM，磺胺

35、间甲氧嘧啶) Sulfonamides AgentsSulfonamides (2) Oral nonabsorbable agentsSulfasalazine(柳氮磺吡啶 ) (3) Topical agents.Mafenide(SML, 磺胺米窿)Sulfadiazine sliver(磺胺嘧啶银)Sulfacetamide(SA,磺胺醋酰）Sulfonamides AgentsSulfonamides (4) Combination agents. Co-trimoxazole(复方新诺明）Trimethoprim(甲氧苄啶) in combination with Sulfamethoxazole(1:5) exerts a synergi