Infectious diseases and Anti-infective drugs (感染性疾病与抗感染药 )

1. Infectious diseases and Anti-infective drugs (感染性疾病与抗感染药)

2. Contents General considerations of anti-microbial agents -Lactam antibiotics （内酰胺类） Macrolides(大环内酯类), lincomycins (林可霉素), and vancomycins (万古霉素) Aminoglycosides (氨基糖苷类) & polymyxins (多粘菌素) Tetracyclines (四环素类) & chloramphenicol (氯霉素) Synthetic antimicrobial agents Anti-fungal agents Anti-viral agents Anti-tuberculosis drugs Clinical uses of antimicrobial agents The drugs treated parasitic infections

3. Contents General considerations of anti-microbial agents -Lactam antibiotics （内酰胺类） Macrolides(大环内酯类), lincomycins (林可霉素), and vancomycins (万古霉素) Aminoglycosides (氨基糖苷类) & polymyxins (多粘菌素) Tetracyclines (四环素类) & chloramphenicol (氯霉素) Synthetic antimicrobial agents Anti-fungal agents Anti-viral agents Anti-tuberculosis drugs Clinical uses of antimicrobial agents The drugs treated parasitic infections

4. Part 1. General considerations of antimicrobial agents

5. Contents • Overview 2. Terms and definition 3. Classification and mechanism of antibacterial action 4. Bacterial resistance

6. 1. Overview: (1)Chemo-therapy(化学治疗, 简称化疗) (2)Chemotherapeutic drugs: Antimicrobial drugs(抗微生物药); Antiparasitic durgs(抗寄生虫药); Antineoplastic drugs(抗肿瘤药). (3)Antimicrobial drugs: Antibacterial drugs(抗菌药); Antifungal drugs(抗霉菌药); Antiviral drugs(抗病毒药).

7. "When I woke up just after dawn on September 28, 1928, I certainly didn't plan to revolutionise all medicine by discovering the world's first antibiotic, or bacteria killer," Fleming would later say, "But I suppose that was exactly what I did." Sir Alexander Fleming (6 August 1881 – 11 March 1955) Fleming, Florey and Chain jointly received the Nobel Prize in Medicine in 1945.

9. Overview (4)The relationship of the host,microorganisms,antimicrobial drugs. Patient drugs (host) Antimicrobial microorganism

10. 2. Terms and definition: (1)Antibacterial drugs(抗菌药): Substances that can kill bacteria and/or inhibit its growth. including: ①Antibiotics(抗生素); ②Synthetic antimicrobial agents,such assulfonamides (磺胺类)andquinolones(喹诺酮类), etc.

11. Termsand definition (2)Antibiotics(抗生素): Substances produced by various species of microorganisms(bacteria, fungi, actinomyces (放线菌), etc.), that can kill or suppressthe growth of other microorganisms.

12. Termsand definition (3)Chemotherapetic index: LD50/ED50orLD5/ED95 (LD: 动物致死量；ED: 治疗感染动物有效量) (4)Antibacterialspectrum(抗菌谱); 广谱 or 窄谱 (5)Bacteriostatic drugs(抑菌药); 抑而不杀 （四环素类、大环内脂类、磺胺类等） (6)Bactericidal drugs(杀菌药); 抑且杀 （青霉素类、头孢菌素类、氨基糖苷类等）

13. agents 抑菌 杀菌

14. Termsand definition (7)Minimum inhibitory concentration (MIC); (8)Minimum bactericidal concentration (MBC): MBC ≥ MIC; if MBC > 32 times MIC  resistance.

15. Termsand definition (No antibacterial drug)

16. Termsand definition (9)Drug resistance (10)Post antibiotic effect(PAE).

17. Classification and mechanism Agents that inhibit synthesis of bacterial cell walls; Agents that act directly on the cell membrane of the microorganism and affect its permeability, and leading to leakage of intracellular compounds; Agents that inhibit protein synthesis; Agents that affect bacterial nucleic acid metabolism; The antimetabolites of folic acid, that can block essential enzymes of folic acid synthetic metabolism.

18. Classification and mechanism 青霉素 头孢菌素 万古霉素 ① ④ 喹诺酮类 利福霉素 ⑤ 红霉素 氯霉素 克林霉素 磺胺类 ③ 四环素类 大观霉素 ② 多黏菌素、制霉菌素 两性霉素B 氨基糖苷类

19. Classification and mechanism (1)Inhibiting synthesis of bacterial cell walls: 青霉素、头孢菌素、万古霉素 UDP-乙酰胞壁酸-5肽 双糖十肽聚合物

20. Classification and mechanism 糖肽聚合物 青霉素、头孢菌素 （ -内酰胺类） -Lactam antibiotics vancomycin transpeptidase 肽聚糖

21. Classification and mechanism (2)Affecting permeability of membrane: ①Ion adsorption 离子吸附 (氨基糖苷类, streptomycin, 链霉素); ②binding to ergosterol (麦角固醇) (amphotercin B, 两性霉素B); ③Inhibiting the synthesis of ergosterol (imidazoles, 咪唑); ④Surface-active agent, that interact strongly with phospholipids (polymixins, 多黏菌素).

22. Classification and mechanism (3)Inhibiting protein synthesis: affecting the function of 30S, or 50S ribosomal (核糖体) subunitstocauseareversibleinhibition of protein synthesis (streptomycin链霉素, erythromycin红霉素, etc.). binding to the 30S ribosomal subunit and altering protein synthesis, which eventually leads to cell death (streptomycin, etc.). Human ribosomal subunits consist 60S & 40S.

23. Classification and mechanism (4)Affecting bacterial nucleic acid metabolism: quinolones喹诺酮类, etc. DNA回旋酶

24. Classification and mechanism (4)Affecting bacterial nucleic acid metabolism: Quinolones喹诺酮类 DNA Top II & Top IV Rifampicin利福平 RNA polymerase Vidarabine阿糖腺苷 Ganciclovir更昔洛韦 Viral DNA replication

25. Classification and mechanism (5)Blocking enzymes of folic acid metabolism: Pteridine(蝶啶)+PABA(对氨苯甲酸) Dihydropteroate synthase Blocked bysulfonamides (磺胺类) Dihydropteroic acid(二氢蝶酸) Glutaminic acid Dihydrofolic acid(二氢叶酸) NADPH Dihydrofolate reductase Blocked bytrimethoprim (甲氧苄啶) NADP Tetrahydrofolic acid(四氢叶酸)

26. 4. Bacterial resistance: (1)Category of resistance: ①Intrinsic resistance 固有耐药 ②Acquired resistance 获得性耐药

27. Bacterial Resistance (2)Mechanism of bacterial resistance: ①to produce enzymes that inactivate antibiotics ②the target is altered; ③to reduce permiabilization of bacterial outer membrane, so that the drug does not reach its target； ④to enhance active efflux system.

28. Mechanism of bacterial resistance ①To produce inactivating enzyme: Production of aminoglycoside modifying enzymes (氨基糖苷类钝化酶) and -lactamase (-内酰胺酶). Avariationof thismechanismisfailure of thebacterialcelltoconvert an inactive drug to its active metabolite.

29. Mechanism of bacterial resistance ②The target is altered: Mutationof the natural target (such as resistance to fluoroquinolone (氟喹诺酮类)). Target modification (ribosomal protection type of resistance to macrolides (大环内酯类) and tetracyclines (四环素)). Substitution with a resistant alternative to the natural, susceptible target (such asmethicillin (甲氧西林) resistance in staphylococci (葡萄球菌)).

30. Mechanism of bacterial resistance ③The drug does not reach its target: Absence of, mutation in, or loss of the appropriate porins(膜孔蛋白) channel can slow the rate of drug entry into the cell, or prevent entry altogether, reducing the effectivedrugconcentrationat thetarget site.

31. Bacterial Resistance Porin channel(膜孔蛋白通道)

32. Mechanism of bacterial resistance ④To enhance active efflux system:

33. Bacterial Resistance (3)The spread of drug resistance: ①Mutations; ②Transduction; ③Transformation; ④Conjugation.

34. Bacterial Resistance ①Mutations(突变): which may occur in the gene encoding: 1)The target protein; 2)The protein involved in drug transport; 3)Act on regulatory gene or promoter(启动子)affecting expression of the target, a transport protein, or an inactivating enzyme. suchas aminoglycosides (氨基糖苷类),quinolones (喹诺酮类),etc.

35. Bacterial Resistance

36. Bacterial Resistance ②Transduction(转导): is acquisition of bacterial DNA from a bacteriophage(噬菌体) that has incorporated DNA from a previous host bacterium within its outer protein coat. Some phages can carry plasmids that code for penicillinase (青霉素酶), or genes encoding resistance to erythromycin (红霉素), tetracycline (四环素), or chioramphenicol (氯霉素).

37. Bacterial Resistance

38. Bacterial Resistance ③Transformation(转化): Uptake and incorporation of DNA that is free in the environment into the host genome by homolgous recombination.

39. Bacterial Resistance ④Conjugation(结合): The passage of genes from cell to cell by direct contact through a sex pilus (性菌毛) or bridging (桥接) is termed conjugation.

40. Bacterial Resistance 转座子：质粒-质粒间、质粒-染色体间互相传播

41. Antibiotics Resistance: A Global Problem!!! MRSA：methicillin resistant staphylococcus aureus 耐甲氧西林金黄色葡萄球菌

42. Part2.-Lactam Antibiotics (-内酰胺类)

43. Classification of-Lactam Antibiotics Ⅰ. Penicillins(青霉素类) Ⅱ. Cepharosporins(头孢菌素类) Ⅲ. Other -lactam antibiotics: 1. Cephamycins(头霉素类) 2. Carbapenems(碳青霉烯类) 3. Monobectams(单环类) 4. Oxacephalosporins(氧头孢烯类) Ⅳ. -lactamase inhibitors(内酰胺酶抑制剂)

44. (青霉素类) (头孢菌素类)

45. (单环类) (碳青霉烯类) (亚胺培南——碳青霉烯类)

46. Ⅰ. Penicillins (青霉素类) A. Natural Penicillin: (酰基侧链) (噻唑烷环) (青霉素类) (-内酰胺环) Chemical structureof penicillins

47. Penicillins 1. Classification of Penicillins: (1)Nature penicillins: Penicillin G(苄青霉素, 简称青霉素) (2)Penicillinase-resistant penicillins: Oxacillin(苯唑西林)、甲氧西林、氯唑西林、双氯西林 etc. (3)Broad-spectrum penicillins: Amoxicillin(阿莫西林)、氨苄西林 etc. (4)Anti-pseudomonas (假单胞菌) penicillins: Ticarcillin(替卡西林)、羧苄西林、哌拉西林 etc. (5)Anti-G- bacilli (杆菌) penicillins: Mecillinam(美西林)、替莫西林 etc.

48. Penicillins 2. Antimicrobial activity: The penicillin-susceptible bacteria: (1)G+ bacilli(革兰阳性杆菌); (2)Non-penicillinase-producing strains of most G- cocci(大多数不产青霉素酶的球菌) & Nisseria(奈瑟菌属), etc. such as:Meningococcus(脑膜炎球菌), Gonococcus(淋球菌), etc. (3)Spirochetes(螺旋体): 梅毒螺旋体、钩端螺旋体、鼠咬热螺旋体etc.

49. Penicillins 3. Mechanism of action: (1)Inhibiting transpeptidase(转肽酶, PBP, 青霉素结合蛋白), and inhibit-ing the synthesis of bacterial cell walls. (2)Activation of cell wall autolytic enzyme(自溶酶).

50. Penicillins Penicillins & cephalosporins can inhibit the transpeptidasereactionin sen-sitive organism (敏感菌). Penicillins