Antimycobacterial drugs （抗结核分枝杆菌药） and antileprotic drugs （抗麻风病药） 2011.12

1. Antimycobacterial drugs（抗结核分枝杆菌药）and antileprotic drugs（抗麻风病药）2011.12

2. Mycobacterium tuberculosis • 亦称结核杆菌: 结核分枝杆菌（M. tuberculosis), 牛分枝杆菌(M. bovis) waxy coating (primarily mycolic acid) M. tuberculosis bacterial colonies

3. Mycobacterium tuberculosis (stained red) in tissue (blue)

4. 形态与染色 • 细长略带弯曲，分枝状，有荚膜，抗酸染色阳性

5. Tuberculosis-related data • tuberculosis：lung, bone, kidney, intestine, lymph node; tuberculous meningitis, … • One third of population infected (?) in the world, with 70% in Asia • Two millions death each year • Chinese patients, 14.3%; Shanghai 5000/year; China > 1.07 million/2009 • World tuberculosis day：March 24, in memory of the day when Robert Koch discovered the bacillus in 1882. Nobel prize in 1905

6. Therapeutic history • Before 1930’s：nutrition therapy：rest, nutrition, fresh air, cure rate 25% • 1930～1950’s： nutrition therapy + physical therapy (artificial pneumothorax), cure rate 40% • Drugs difficulty in entering the cells • 1950’s：streptomycin, isoniazid, rifampicin；cure rate >90% • 21 century：multidrug resistance, TB incidence ↑

7. The evolution of antitubercular agents The discovery of the antitubercular activity of aminoglycoside antibiotics streptomycin by Waksman et al in 1944 ushered in the modern era of tuberculosis treatment.

8. 1952, p-amino-salicylic acid(PAS) • 1952, isoniazid • Ethambutol • 1959, rifampicin

10. Anti-TB drugs • First-line drugs: Isoniazid（异烟肼） Rifampicin（利福平） Ethambutol（乙胺丁醇） Pyrazinamide（吡嗪酰胺） Streptomycin（链霉素） • Second-line drugs: Ethionamide（乙硫异烟胺） Para-aminosalicylic acid（对氨水杨酸） rifapentine（利福喷丁） sparfloxaxcin（司帕沙星）

11. Isoniazid 异烟肼

12. isoniazid • discovered in 1912 • 1951, found to be effective against tuberculosis • never used on its own because resistance develops quickly

13. Mechanism of isoniazid • Prodrug • activated by bacterial catalase（过氧化氢酶）-peroxidase（过氧化物酶） enzyme called KatG • KatG couples the isonicotinic acyl with NADH（烟酰胺腺嘌呤二核苷酸，辅酶I） • form isonicotinic acyl-NADH complex • complex binds tightly to ketoenoylreductase（酮烯醇还原酶） • blocking the natural enoyl-AcpM substrate and the action of fatty acid synthase （acyl carrier protein) • the processinhibits the synthesis of mycolic acid（分枝菌酸）, required for the mycobaterial cell wall.

14. Mechanism of action InhA catalyzes the NADH-dependent reduction of 2-trans-enoyl-ACP’s and is involved in the biosynthesis of mycolic acid, a critical component of the mycobacterial cell wall. This enzyme is the target for the anti-tubercular drugs isoniazid and ethionamide （乙硫异烟胺）

15. Pharmacogenetic consideration

17. Side effects of isoniazid ① Peripheral neuropathy（外周神经炎）；CNS excitement INH → Vit B6↓→ GABA↓→ CNS excitement seen in slow acetylation，Vit B6 prevention ② hepatic injury acetylated products—monoacetyl isoniazid（liver toxic） seen in rapid acetylation，hepatic function test needed

18. rifampicin（利福平）

20. discovery of rifampicin • 1957，soil from pine wood, French Riviera • Piero Sensi, Italy, found new bacterium • Researchers fond of French crime story Rififi (about a jewel heist and rival gangs ) • Named “Rifamycins” • 1959, rifampicin discovered

21. Actions and mechanism • Anti-bacterial spectrum： • Mycobacterium tuberculosis; Mycobacterium leprae（麻风分枝杆菌） • Gram-positive and Gram-negative bacteria • Cytochrome 450 inducer: CYP2C9 and CYP3A4 • Inhibitor of prokaryotic （原核） DNA-primed RNA polymerase

22. Clinical uses of rifampicin • tuberculosis • leprosy • Infections caused by G+ or G－ bacteria including resistant S. aureus • Trachoma（沙眼），Conjunctivitis（结膜炎）

23. Side effects of rifampicin • Liver toxicity • Allergic reaction • Teratogenesis • Red metabolites appearing in feces, urine, sweat, tear, sputum

24. Ethambutol（乙胺丁醇）

25. ethambutal • Mechanism: disrupting arabinogalactan（阿拉伯半乳聚糖） synthesis by inhibiting the enzyme arabinosyl transferase, leading to increased permeability of the cell wall. • Side effect: optic neuritis（视神经炎）, dose and time related

26. Pyrazinamide（吡嗪酰胺）

27. pyrazinamide • killing the bacteria inside the cells, especially in acidic situation • Liver toxic (long term use)

28. streptomycin • Listed in aminoglycosides （氨基糖苷类） • Used when bacteria produce resistance to other durgs

29. Second-line drugs • Ethionamide（乙硫异烟胺）

30. Para-aminosalicylic acid（对氨水杨酸）

31. Rifapentine（利福喷丁）

32. TB therapeutic principles • Early use • Combination therapy (always), usually 4 drugs • Enough doses, regular and long term（６months or more)

33. Why combination therapy • A major advance in the treatment of tuberculosis was signaled by the introduction of the antibiotic rifampin into therapy. • Clinical studies: rifampin is included in the regimen, particularly in combination with isoniazid and ethambutol (or pyrazinamide), the period required for successful therapy is shortened significantly( 6-9 months, 2 ys without rifampin).

34. Antileprotic drugs 抗麻风病药

35. Biology of M. leprae • Morphology and staining ≈ M. tuberculosis • Living inside the cells——Leprosy cells • In vitro culture unsuccessful • Previously vaccinated in armadillo（犰狳） • Now in the naked mice 犰狳

36. Leprosy pathogenic data • Spreading modes • Respiratory tract（main） • Direct contact • Slow onset, lasting long • Nerve and skin mainly invaded • 6603 patients in 2009 in China • Distribution:云南、贵州和四川

37. Drugs used for leprosy Dapsone（氨苯砜） Inhibiting bacterial synthesis of dihydrofolic acid of Mycobacterium leprae First choice in treating leprosy patients

38. Thalidomide（沙利度胺） Combined use with other anti-leprosy drugs

39. >10000 baby in 46 countries were born with deformities 1962 photo of a baby born to a mother who had taken thalidomide while pregnant; note the extra appendage connected to the foot and the malformation of the right arm.

40. Frances Oldham Kelsey, MD, US FDA inspector, pharmacologist • Refused FDA to approve • more study was needed • Richardson Merrell gave the tablets to doctors on the understanding that the drug was still under investigation • 17 were born with the deformities • 1962, US laws, safety test during pregnancy

41. 1962: FDA inspector Frances Oldham Kelsey receives an award from President John F. Kennedy for blocking sale of thalidomide in the United States

42. 阅读材料：Dover LG, Coxon GD. Current status and research strategies in tuberculosis drug development. J Med Chem 2011; 54(18):6157-65

43. Anti-fungal drugs 抗真菌药

44. Dermatophytes（皮肤癣菌）

45. Biology of fungus • Fungus: heterogeneous organisms（异养生物） with eukaryotic and cell wall • 300,000 kinds of fungi, only 270 of which cause disease in humans and animals • Systemic fungal infections（深部感染）: organ and tissue infections: Candida albicans（白念珠菌）； Cuyitococcus Neofonmans (新型隐球菌）；… • Topical fungal infections（表浅部感染）: ringworm（癣）

46. 足癣 体癣

47. 体癣

48. 头癣

49. Fungal infections In recent year, the incidence of fungal infections has reached alarming proportions. This duo to a number of factors .

50. Development of anti-fungal drugs • 1903，Beurmann: potassium iodide for Sporotrichosis（孢子丝菌病） • 1939，griseofulvin（灰黄霉素） discovered by British scientist • 1950’s, nystatin（制菌霉素）; amphotericin B（两性霉素B） • 1960’s, azolee（唑类）：fluconazole（氟康唑），itraconazole（伊曲康唑），… • 2000’s, caspofungin（卡泊芬净）; micafungin（米卡芬净），…