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Chapter 19 Antimicrobial Agents

Chapter 19 Antimicrobial Agents. 主讲：乔春华 ２００９－５－２１. MIC : Minimum Inhibitory Concentration ( 最小抑制浓度 ) The smallest concentration that will prevent visible microorgnism growth MIC 99 , MIC 50 t ½ : half life, a general term ( 半衰期 )

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Chapter 19 Antimicrobial Agents

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  1. Chapter 19 Antimicrobial Agents 主讲：乔春华 ２００９－５－２１

  2. MIC: Minimum Inhibitory Concentration (最小抑制浓度) The smallest concentration that will prevent visible microorgnism growth MIC99, MIC50 t ½: half life, a general term (半衰期) The time for a drug to lose half of its pharmacologic activity Serum Protein Binding: two factors (血浆蛋白结合) 1. The percentage of antibiotic（drug） binding 2. The tightness of binding An antibiotic that is not significantly protein-bound will normally be rapidly excreted and have a short half-life; Some protein binding of poorly water-soluble agents is normally regarded as helpful; The urine is a protein-free filtrate so that an antibiotic that is firmly bound to serum proteins will be retained in the blood.

  3. Gram positive Vs gram negative bacteria 革兰氏阳性Vs革兰氏阴性菌 Gram positive cell wall Gram negative cell wall • Danish scientist : Hans Christian Gram, (1853 – 1938), • Developed in 1884 • Discriminate between two types of bacteria with similar clinical symptoms: • Streptococcus pneumoniae , Klebsiella pneumoniae bacteria

  4. Gram negative Thinner Additional outer membrane, contain lipids Stain pink Gram positive Thick, mesh like cell wall Made of peptidoglycan Stain purple Gram(+)infection is an infection caused by Gram(+) microorganism

  5. Section 1 Synthetic Antimicrobial Agents Molecular mode of action : target key enzymes needed for the biosynthesis of nucleic acids

  6. Section 1 Sulfonamides: 磺胺类药物 1932， 磺胺米柯定, 百浪多息 Red dye 1932, Domagk Active in vivo Inactive in vitro Active substance Colorless 1938 Nobel Prize Winner for Medicine

  7. Mechanism of Action作用机理 Sulfonamides PABA Molecular size and electron density similarity PABA: p-aminobenzoic acid A structural component of folic acid derivatives Sulfonamides can compete with PABA

  8. Biosynthetic site of action of sulfonamides 二氢蝶啶 DNA 脱氧胸腺嘧啶苷 Dihydrofolic acid, 二氢叶酸 磺胺药物在细菌生物合成DNA中的作用位点

  9. 代谢拮抗 False Metabolite formation by sulfanamide

  10. Structure-activity Relationships (构效关系) pKa 6.5 pKa 10.4 Sulfamethoxazole 磺胺甲噁唑 Sulfadiazine 磺胺嘧啶 Increased antibacterial potency, water solubility under physiologic conditions

  11. Sulfamethoxazole Sodium sulfamethoxazole • Water solubility: Occasional crystallization in the urine, kidney damage. • Urine pH 7.0 • Broad antimicrobial spectrum • Good absorption and distribution

  12. Synthesis of Sulfamethoxazole

  13. 3. SAR of sulfonamides 2. Structure-Activity Relationship & Mechanism • 氨基与磺酰基在苯环上必须互成对位（Para position）； • 苯环用其它环代替，或在苯环引入其它基团，抑菌作用降低或失去； • SO2NH2基团被SO2C6H4(p-NH2), SOC6H4 (p-NH2), CONH2, CONHR, COC6H4R等取代，则抑菌作用降低； • 磺酰氨基N-取代抑菌作用增强，杂环取代抑菌作用明显增加

  14. Trimethoprim: Antibacterial Synergist （抗菌拮抗剂） 甲氧苄啶 Commonly used in a 1:5 fixed ratio with the sulfonamide

  15. Trimethoprim: Antibacterial Synergist （抗菌拮抗剂） 甲氧苄啶 DNA Site of action of trimethoprim

  16. （协同效应） Synergistic Effect • Synergy is the term used to describe a situation where different • entities cooperate advantageously for a final outcome. • Simply defined, it means that the whole is greater than the sum of its parts. 1 + 1 > 2

  17. Synthesis of Trimethoprim

  18. Section 2 Quinolones（喹诺酮） 1. History First-generation 第一代 砒咯酸 萘啶酸，First marketed quinolone drug, 1962 Primarily effective against Gram (―) bacteria Mainly used to protein free compartments, such as the urinary tract Comparatively low potency Narrow spectrum Short half life Some toxicity to central nerve system

  19. Second-generation 第二代 砒哌酸 Structure : basic piperidinyl group at 7 position Increase molecular basic property, water solubility, 增加水溶性。 Broader spectrum， 抗菌谱广。 Reduced side effect，降低副作用。 Attenuated pharmacology property，药代动力学性质改善。

  20. Third generation 第三代 环丙沙星 氧氟沙星 诺氟沙星 洛美沙星 依诺沙星 左氧氟沙星 F atom at 6 position, piperidinyl substitute at 7 position Broader spectrum, effective for both Gram(+) and Gram(-) (抗菌谱广) High potency (抗菌活性高） Good pharmacology kinetic (PK) parameter （良好药代动力学参数）

  21. Mechanism of action of Quinolones Inhibition of DNA gyrase and topoisomerase IV (抑制DNA回旋酶和拓扑异构酶） Alter the degree of twisting of DNA and releases torsional stress in the molecule Makes a cell’s DNA inaccessible and leads to cell death.

  22. Quinolones Chemical Incompatabilities • Chelate polyvalent metal ions: Ca2+, Mg2+, Al3+ and Fe2+ • Form less water-soluble complexes • Lose considerable potency

  23. Structure-Activity Relationship Core structure R1: change antibacterial potency Position 3 and 4: pharmocophore, also chelate polyvalent metal ion Position 6: potency trend is : F>Cl>CN»NH2»H Position 7: relevant to antibacterial potency, piperidinyl is best Position 8: relevant to light caused toxicity

  24. Synthesis of ciprofloxacin （环丙沙星）

  25. Synthesis of levofloxacin　（左氧氟沙星）

  26. Summary: sulfonamides （磺胺） Site of Action: Inhibit dihydropteroate synthase and dihydrofolate reductase -----folic acid biosynthesis------DNA

  27. Summary: Quinolones （喹诺酮） Mechanism of Action: Inhibition of DNA gyrase and topoisomerase IV (抑制DNA回旋酶和拓扑异构酶）

  28. Section 3 Tuberculostatics （抗结核药物） TB is a disease which mainly affects the lungs

  29. Tuberculosis • A chronic bacterial infection caused by the Mycobacterium tuberculosis • 由结核杆菌引起的慢性传染病 • Tuberculosis is one of the leading worldwide • cause of mortality 全球范围内最主要的致死性传染疾病之一 • Most alarming is the emergence of multidrug- • resistant tuberculosis (MDR-TB) 抗多药耐药结核菌 • Coinfection with AIDS virus • 与艾滋病毒的共感染 M. Tuberculosis cell wall

  30. Drug Therapy―Tuberculosis First-line Agents 一线药物 Isoniazid (Isonicotinic Acid Hydrazide, INH) 异烟肼 Syntheis of isoniazid

  31. Mechanism of Action: Acylating intermediate Reaction products formed from catalse-peroxidase reaction with INH 过氧化氢酶-过氧化物酶与异烟肼的反应生成物

  32. Mechanism of action Mycolic acid Enoylthioester reduction catalyzed by NADH and inhA

  33. Structure-activity Relationships Isonicotinic acid hydrazides Isoniazid hydrazones Isoniazid hydrazones possess activity, unstable in the G.I. tract Active component is INH Substitution on the N2 position resulted in active compounds Substitution of the N1 with alkyl groups destroyed the activity

  34. Metabolism of isoniazid，异烟肼的代谢 major toxic

  35. Chemical incompatability pH < 7 Red complex pH 7.5

  36. Ethambutol hydrochloride （EMB） 盐酸乙胺丁醇 • Inhibit the biosynthesis of bacteria cell wall • Combined with isoniazid • Metabolized by oxidation reaction:oxidation of alcohol to aldehyde, acid

  37. Site of action of ethambutol (EMB) in cell wall synthesis 阿拉伯糖基转移酶 β-D-arabinofuranosyl-1-monophosphoryldecaprenol The Mycobacterium have a unique outer envelop consists of arabinofuranose （阿拉伯呋喃糖）and galactose (AG， 半乳糖), which is covalently attached to the peptidoglycan and an Intercalated framework of lipoarabinomannan (LAM) EMB 抑制阿拉伯糖基转移酶，导致AG和LAM的合成受阻，最终影响结核菌细胞壁的合成。

  38. Metabolism of ethambutol 乙胺丁醇的代谢 • The majority of the orally administered ethambutol is excreted unchanged (73%) • 73%的药物以原药的形式排出 • No more than 15% appearing in the urine as either Metabolite A, or Metabolite B • 约15% 以代谢物A或代谢物B的形式从尿中排出 • Both metabolite are devoid of biologic activity • 两种代谢物都没有生物活性

  39. 二 Antibiotics—Streptomycin (STM) 链霉素 • The first biologically active aminoglycoside氨基糖苷 • Water soluble with basic properties • Orally administered STM is recovered unchanged • from the feces indicating that the lack of biologic • results from poor absorption and not chemical degradation Waksman developed STM in 1944

  40. Mechanism of Action （作用机制） • The mechanism of aminoglycosides in general has not been fully elucidated (氨基糖苷的作用机制不是非常明确） • STM is known to inhibit protein synthesis, additional effects on misreading of a m-RNA template and membrane damage（STM能 够抑制蛋白质的合成，此外还对读错m-RNA模版和膜损伤方面有作用） • In STM resistant organisms: • ribosomal protein S12 protein undergoes a change in which the lys43 and • Lys88 are replaced with Arg and Thr. • The pseudoknot conformation of 16S rRNA which results from intramolecular • base pairing between GCC bases in regions 524-526 of the rRNA to CGG • bases in regions 505-507 is perturbed.

  41. Structure-activity Relationship of STM kanamycin neomycin paromomycin streptomycin 新霉素 卡那霉素 巴龙霉素 链霉素 • All aminoglycosides have similar pharmacologic, pharmacodynamic and toxic property 所有氨基糖苷类化合物都有相似的药理、药代动力学和毒性性质 • Only streptomycin and kanamycin are used to treat tuberculosis, indicating the narrow band of structurally allowed modification 只有链霉素和卡那霉素对结核杆菌有效，提示结构修饰的空间很小

  42. Structure-activity Relationship of STM STM

  43. Metabolism of STM • 50-60% dose is recovered as unchanged drug in the urine • No human metabolites of STM have been isolated • Adenylation of the C-3 hydroxyl group gives O-3-adenylate metabolite • Phosphorylation C-3 hydroxyl gives O-3-phosphorylate metabolite. Major pathway

  44. Macrolides （大环内酰胺） 1 Rifamycin Antibiotics利副霉素 Natural product produced by Streptomyces mediterranei （链丝菌）

  45. Mechanism of Action • The rifamycins inhibit bacterial DNA-dependent RNA polymerase 抑制依赖于DNA的RNA聚合酶 • Binding to the β-subunit of the enzyme 与酶的β-亚单元结合 • Rifampin is active against DDRP from both gram-(+) and gram-(-) bacteria 对革兰氏阳性及阴性菌均具有活性 • Inhibition of DDRP leads to a blocking of the initiation of chain formation in RNA synthesis 阻断RNA合成中的链起始 DDRP

  46. Structure-activity Relationship • Free –OH groups are required at C-1, 8, 21and 23 • The OH groups appear to lie in a plane and appear to be important binding groups for attachment to DDRP • Reduction of the double bonds in the macro ring results in a progressive decrease in activity • Opening of the macro ring also gives inactive compounds.

  47. Rifampin (RIF) Rifamycin 利福平 Introduced in 1967 • With 32 times potency compared to rifamycin • Oral treatment of TB was reduced from 18 to 9 months • Potentially hepatotoxic • May produce gastrointestinal disturbances, rash • Rifampin is nearly always used in combination with one or more other antiTB agents

  48. Rifapentine （利福喷丁） Rifapentine Rifapin • More active compared to Refampin • Orally administered twice/week • 97.7% is bound to plasma protein • Longer half life, 13h • Orally administered twice/day • 80% is bound to plasma protein • Short half life, 2-5 h

  49. Physical Chemical Properties • Rifampin and rifapentine are red-orange crystalline compounds • Zwitterionic property because of the presence of the phenolic groups(acidic) and the piperazine basic property • Compounds are prone to acid hydrolysis, giving 3-formyl-rifamycin SV • Compounds are prone to air oxidation, para phenolic group to p-quinone • Metabolites are excreted in the urine, feces, saliva, sweat and tears

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