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1 Lecture 6-2 Microbial Growth Control in vitro and in vivo Chapter 26 in Brock Biology of Microorganisms Zhao Liping and Chen Feng School of Life Science and Biotechnology

2 III. ANTIMICROBIAL AGENTS USED IN VIVO 体内使用的抗微生物制剂 Selective toxicity 选择毒性 Can be used internally 可体内使用 Chemotherapeutic agents 化学治疗剂

3 Chemotherapeutic agents can be categorized based on their structure 基于化学结构的化学治疗剂分类烃类大环内脂利福平醌类链霉素丝裂霉素

4 氨基酸与肽类似物含氮杂环类多氧菌素含氧杂环类莫能菌素

5 环脂类芳香类灰黄霉素脂肪类放线菌酮磷霉素

6 喹诺酮类噁唑类

7 Mode of action of antibacterial agents FLASH 中文名

8 Actinomycin 放线菌素

9 Rifampin 利福平

10 Streptomycin 链霉素

11 Tetracyclin 四环素

12 Chloramphenicol 氯霉素

13 Puromycin 嘌呤霉素

14 Erythromycin 红霉素

15 Penicillin G

16 Characteristic spectrum of antibacterial action of different agents 每种抗生素都有其特定的抗菌谱

17 Synthetic Antimicrobial Drugs 人工合成的抗微生物药物

18 6.6.1 Growth Factor Analogs: Sulfa Drugs 磺胺类药物 Growth factor analogs: compounds that are structurally similar to the growth factors, but their structural differences prevent them from duplication the function of the natural growth factor in the cell. 生长因子类似物 : 与生长因子的结构相似, 但不具有生长因子的功能. G. Domagk

19 The sulfa drugs were the first widely used growth factor analogs to specifically inhibit the growth of bacteria. 磺胺类药物

20 Sulfanilamide is an analog of p-aminobenzoic acid, which is a part of the vitamin folic acid. Sulfanilamide acts by blocking the synthesis of folic acid, a nucleic acid precursor. 磺胺是对氨基苯甲酸的类似物, 可阻断叶酸的合成.

21 Sulfanilamide is active in bacteria but not in higher animals,why? Bacteria synthesize their own folic acid, whereas higher animals obtain folic acid from their diet. 细菌自己合成叶酸, 而高等动物从饮食中获取叶酸.

22 6.6.2 Other Growth Factor Analogs Isoniazid, a nicotinamide (vitamin) analog, is effective only against Mycobacterium tuberculosis, 异烟肼, 烟碱的类似物, 仅作用于结核分支杆菌. Mechanism: interfere with the synthesis of mycobacterial-specific mycolic acid 影响分支杆菌特异性的分支菌酸合成,

23 Amino Acid Analogs Nucleic Acid Analogs

24 6.6.3 Quinolones 喹诺酮 A class of synthetic antibacterial compounds that interact with bacterial DNA gyrase 喹诺酮类物质作用于细菌的 DNA 促旋酶, Mechanism: It prevent the gyrase to form supercoiling bacterial DNA. 使细菌 DNA 不能形成超螺旋.

6.7 Antibiotics: Naturally occurring antimicrobial drugs 抗生素 Antibiotics: Chemical substances produced by certain microorganisms that inhibit or kill other

25 6.7 Antibiotics: Naturally occurring antimicrobial drugs 抗生素 Antibiotics: Chemical substances produced by certain microorganisms that inhibit or kill other microorganisms 1. Broad-spectrum antibiotics: act on both G+ and G- Bacteria 广谱抗生素 2. Narrow-spectrum antibiotics: act on only a single group of organisms. 窄谱抗生素

26 Annual worldwide production of antibiotics

27 Major groups of antibiotics b-lactam antibiotics b- 内酰胺类 produced by fungi (and some certain bacteria) penicillins, cephalosporins, cephamycins 青霉素, 头孢菌素, 头霉素 inhibitors of cell wall synthesis Aminoglycoside antibiotics 氨基糖苷类 Structure streptomycin, kanamycin, gentamicin, neomycin 链霉素, 卡那霉素, 庆大霉素, 新霉素 inhibit protein synthesis at the 30S subunit of the ribosome Structure

28 Major groups of antibiotics (2) Macrolide antibiotics 大环内脂类 Structure erythromycin, oleandomycin, spiramycin, tylosin 红霉素, 竹桃霉素, 螺旋霉素, 泰乐菌素 inhibit protein synthesis at the 50S subunit of the ribosome Tetracyclines 四环素类 broad spectrum (act on both G+ and G- bacteria) inhibit protein synthesis at the 30S subunit of the ribosome Structure

29 16.3 Antifungal drugs (fungicides) Fungi are Eukarya, so chemotherapeutic agents that affect metabolic pathways in fungi often affect corresponding pathways in host cells, resulting in drug toxicity. 真菌为真核生物, 可影响真菌代谢的化学药物往往可影响寄主代谢, 产生药物毒性.

30 Sites of action of some antifungal chemotherapeutic agents 抗真菌药的作用位点

31 Example: Ergosterol inhibitors 麦角固醇抑制剂 In most fungi, ergosterol replaces the cholesterol found in higher eukaryotic cell membranes. 真菌以麦角固醇代替高等真核生物细胞膜中的胆固醇. Polyenes: can bind to ergosterol and disrupts membrane function, eventually cause membrane permeability and cell death. 多烯烃 Azoles and allylamines: selectively inhibit ergosterol biosynthesis and therefore have broad antifungal activity. 氮杂茂及丙烯胺

32 IV. ANTIMICROBIAL DRUG RESISTANCE AND DRUG DISCOVERY 抗药性与新药研制

33 6.8 Antimicrobial drug resistance Drug resistance: acquired ability of an organism to resist the effects of a chemotherapeutic agent to which it normally susceptible 抗药性 Most antimicrobial resistance involves resistance genes that are transferred by means of genetic exchange. 多数抗药性的产生与抗性基因转移有关

34 Antibiotic resistance of producers To protect themselves, antibiotic producers develop resistance mechanisms to neutralize or destroy their own antibiotics; 为保护自身, 抗生素产生菌可发展出抑制或破坏本身抗生素的抗性机制 ; Genes encoding these resistance mechanisms can occasionally be transferred to other organisms. 与抗性机制有关的基因有时会转移到其它生物.

35 Antibiotic Resistance mechanisms 1. Lack the structure that an antibiotic attacks Mycoplasmas do not have cell wall and resistant to penicillins 2. Impermeable to antibiotic Gram negative bacteria impermeable to penicillin G 3. Ability to alter the antibiotic to an inactive form staphylococci produce b-lactamase to cleave the b- lactam ring

36 Antibiotic Resistance mechanisms 4. Modification of the target of the antibiotic Ribosome alteration 5. Alteration of the metabolic pathway that inhibited by antibiotic folic acid synthesis folic acid uptake 6. Pumping out of antibiotics (efflux)

37 Genetic characteristics of resistant genes 抗性基因的遗传学特征 Chromosome-encoded resistance 染色体编码的抗性 Resistant mutant that screening in Laboratory is usually due to mutations in chromosomal genes. Mechanism: In most cases, the resistance arises because of a modification of the target of antibiotic action (e.g. ribosome) difficult to transfer between cells 不易转移 Plasmid encoded resistance-r plasmid 质粒编码的抗性 mostly from patients Mechanisms: enzymes to inactivate the antibiotics; inhibition of uptake into the cell; pumping out from the cell

38 Where did the R plasmids come from? Were they the result of antibiotic era?

39 Origin of resistance plasmids R plasmid existed before the antibiotic era!!! R 质粒在抗生素时代之前就已存在 Evidence: a strain of E. coli that was freeze dried in 1946 was found to contain a plasmid with resistance to tetracycline and streptomycin, several years before these antibiotics were used clinically R plasmids have been detected in some nonpathogenic gram-negative soil bacteria

40 Spread of antimicrobial drug resistance Resistant microorganisms are selected by the presence of the antibiotic in the environment 抗性微生物的选择压力 : 环境中存在抗生素 Drug resistance develops rather quickly among clinical isolates

42 Relationship between use of antibiotic and development of resistance Those agents that have been used in the largest amounts are those for which drug-resistant strains are most frequent.

Percentage of reported cases of gonorrhea caused by drugresistant strains 由抗药菌株引起的淋病病例百分比 59000 9000 Greater than 95% of the reported drug-resistant cases are due to

43 Percentage of reported cases of gonorrhea caused by drugresistant strains 由抗药菌株引起的淋病病例百分比 Greater than 95% of the reported drug-resistant cases are due to penicillinase-producing strains of Neisseria gonorrhoeae 淋病奈瑟氏菌. Since 1990, penicillin has not been recommended for treatment of gonorrhea because of emerging drug resistance.

Development of drug resistance in human pathogens 人类致病菌的抗药性发展过程 *symbol indicates that some multi-drug resistant strains are now untreatable with known antimicrobial drugs

45 Development of drug resistance in human pathogens 人类致病菌的抗药性发展过程 *symbol indicates that some multi-drug resistant strains are now untreatable with known antimicrobial drugs 表示存在现有抗生素无法治疗的多抗性菌株 Acinetobacter 不动杆菌属 Enterococcus 肠球菌属 Streptococcus 链球菌属 Mycobaterium 分支杆菌属 Staphylococcus 葡萄球菌 Shigella 志贺氏菌属 Salmonella 沙门氏菌属 Pseudomonas 假单胞菌属 Neisseria 奈瑟菌属 Haemophilus 嗜血菌属

46 Reasons for rapid development of drug resistance 1. Antibiotics are used far more than is necessary 80% use for 20% necessary 滥用 50% incorrect dose or duration 错用 Antibiotics are used as growth-promoting substances and as prophylactics in animal feeds 作为生长促进剂和预防药在动物养殖中使用 Especially in Asia, include China

47 Reasons for rapid development of drug resistance 2. Patient noncompliance 不遵医嘱 Stop medication prematurely. (Many patients stop taking antibiotics as soon as they feel better.) 过早停药 Leaving pathogen to sub-lethal dose for short period selection of resistant strains 致病菌处于亚致死剂量时易产生抗药株

48 Reversing of antibiotic resistance The Hungary case early 1980s, 50% resistance to penicillin , penicillin use decreased by half Resistant strains decreased from 50% to 34% Results: If the use of a particular antibiotic is stopped, the resistance to that antibiotic will be reversed over time. Thinking and Discussing: why?

49 Thinking The relationship between antimicrobial consumption in human communities and the frequency of resistance

50 Cliker Questions

51 Which of the following statements is true? a. Thermal death time depends on the size of the population tested. b. Decimal reduction time depends on the initial cell concentration. c. Thermal death time is independent of the size of the population tested. d. all of the above

52 Which of the following statements about autoclaves is not true? a. The pressure inside the autoclave kills the microorganisms. b. The high temperature in the autoclave kills the microorganisms. c. If a bulky object is being sterilized, the total heating time must be extended because heat transfer to the interior is retarded. d. Large volumes of liquid take longer to reach sterilization temperatures.

53 a. the amount of microbial agent added to the disc. b. the diffusion coefficient. c. the solubility of the agent. d. all of the above The diameter of the zone of inhibition created during the disc diffusion technique is proportional to

54 The diameter of the zone of inhibition created during the disc diffusion technique is proportional to a. the amount of microbial agent added to the disc. b. the diffusion coefficient. c. the solubility of the agent. d. all of the above.

55 Which of the following statements about pasteurization is not true? a. Pasteurization reduces the microbial load in heat-sensitive liquids. b. Pasteurization is a method of sterilization. c. Pasteurization controls Salmonella. d. Pasteurization increases the shelf life of perishable liquids.

by mild (22.7%). Inhaled corticosteroids, systemic corticosteroids, and antibiotics were applied to 94.8% (292 cases), 74.7% (230 cases), and 90.9% (2

by mild (22.7%). Inhaled corticosteroids, systemic corticosteroids, and antibiotics were applied to 94.8% (292 cases), 74.7% (230 cases), and 90.9% (2 论著临床研究 doi: 0.7499/j.issn.008-8830.204.2.007 郑州市城区儿童哮喘的流行病学调查及发病相关因素分析赵坤宋桂华古华倩 2 刘爽 3 张岩郭彦荣 (. 河南中医学院第一附属医院儿科医院, 河南郑州 450000; 2. 杭州市余杭区