药理学南开大学第三十五章抗微生物药物概论

1、Antimicrobial AgentsGeneral Considerations Medical school of Nankai UniversityJingling zhang and Jing Li药理学南开大学第三十五章抗微生物药物概论Antimicrobial Agents目的 了解化学治疗的含义及抗菌药的发展简史。掌握有关抗菌药物的常用术语和各类抗菌药物的抗菌作用原理，细菌耐药性产生的机制。药理学南开大学第三十五章抗微生物药物概论Antimicrobial Agents内容化学治疗的涵义，药物、宿主和致病病原体三者的相互关系。抗菌药的创立及其发展简史。抗菌药的常用术语：抗菌谱、

2、耐药性和化疗指数的概念及其意义。细菌的结构及其功能。药理学南开大学第三十五章抗微生物药物概论Antimicrobial Agents常用抗菌药的作用原理：抑制细菌叶酸代谢：磺胺药及其增效剂。影响细菌细胞壁的合成：青霉素及头孢霉素。影响细菌蛋白质的合成：链霉素、红霉素、四环素类和氯霉素。影响细菌细胞浆膜的功能：多粘菌素、制霉菌素和二性霉素B。细菌耐药性产生的机制：合成破坏抗生素的酶，改变细胞膜的通透性，改变药物作用的靶结构，改变细菌的代谢途径。药理学南开大学第三十五章抗微生物药物概论Antimicrobial Agent IntroductionDefinitions and Character

3、isticsAntimicrobial mechanismsResistance to antimicrobial drugs药理学南开大学第三十五章抗微生物药物概论HEREIntroductionChemotherapeutic agents are chemicals (either natural or synthetic) used to inhibit the growth of malignant or cancerous cells within the body & to be toxic for the infectious organism but innocuous fo

4、r the host.药理学南开大学第三十五章抗微生物药物概论HEREIntroductionAnti-infective agents are chemical substances that can kill or suppress the growth of microorganisms. Antibiotics are soluble compounds that are derived from certain microorganisms and that inhibit the growth of other microorganisms. The term antibiotic

5、s include synthetic antibacterial agents, such as the sulfonamides and quinolones, which are not products of microbes.药理学南开大学第三十五章抗微生物药物概论HEREIntroductionThe major groups of antibacterial agents include:Sulfonamides Penicillins and Cephlosporines (betalactams) Aminoglycosides Tetracyclines and Chlor

6、amphrnicol Erythromycin, Clindamycin and Vancomycin, etc. 药理学南开大学第三十五章抗微生物药物概论Antimicrobial Agent IntroductionDefinitions and CharacteristicsAntimicrobial mechanismsResistance to antimicrobial drugs药理学南开大学第三十五章抗微生物药物概论HEREDefinitions and CharacteristicsSelective toxicityRelative selective toxicity B

7、acteriostatics BactericidalsChemotherapeutic index Antimicrobial activityAntibiotic spectrum MICMBCPAE It implies that the drug is harmful to a parasite without being harmful to the host. An ideal antimicrobial drug exhibits selective toxicity. It means that a drug may damage a parasite in a concent

8、ration that can be tolerated by the host.This term describes a drug that temporarily inhibits the growth of a microorganism. The term describesa drug that attachesto its receptor &causes the death ofthe microorganism. Typical bactericidaldrugs are the -lactams & theaminoglycosides. The effect isreve

9、rsible: when thedrug is removed, theorganism will resumegrowth & infection ordisease may recur. The typicalbacteriostatic drugsare the sulfonamides& tetracyclines. Chemotherapeutic index: The terms bacteristatics and bactericidal are relative, not absolute. Sometimes prolonged treatment with bacteri

10、ostatic drugs can kill certain microbial populations (eg. Chloramphenicol and meningcocci), whereas bactericidal drugs may fail to do so (eg. penicillin G and enterococci), both in vitro and in vivo.药理学南开大学第三十五章抗微生物药物概论HEREDefinitions and CharacteristicsSelective toxicityRelative selective toxicity

11、Bacteriostatics BactericidalsChemotherapeutic indexAntimicrobial activityAntibiotic spectrum MICMBCPAE It is the ability of antimicrobial agent inhibiting or killing microorganisms. It is the antimicrobial range of antibacterial agent. (narrow, broad) MIC： Minimum inhibitory concentration MBC： Minim

12、um bactericidal concentration PAE (postantibiotic effect ) It is a residual bactericidal activity persisting after the serum concentration has fallen below the minimum inhibitory concentration. 药理学南开大学第三十五章抗微生物药物概论HEREDefinitions and CharacteristicsThe effectiveness of antimicrobial agents usually r

13、elies on a biochemical or physiologic difference between the host and the parasite. Antimicrobial drugs can differ from one another in the following ways: Chemical properties Mechanism of action Pharmocokinetics Spectrum of activity (Antimicrobial Activity) Therapeutic uses Untoward effects药理学南开大学第三

14、十五章抗微生物药物概论Antimicrobial Agent IntroductionDefinitions and CharacteristicsAntimicrobial mechanismsResistance to antimicrobial drugs药理学南开大学第三十五章抗微生物药物概论HEREAntimicrobial mechanismsFor a majority of antimicrobial drugs, the mechanism of action is not completely understood. However, for purposes of dis

15、cussion, it is convenient to present antimicrobial mechanisms under 4 distinct headings:药理学南开大学第三十五章抗微生物药物概论Inhibition of cell wall synthesisAlteration in the permeability of cell membrane or active transport across cell membraneInhibition of protein synthesis (ie. inhibition of translation and tran

16、scription of genetic material)Inhibition of nucleic acid synthesisHEREAntimicrobial mechanismsQuinolones Block action of DNA gyrasePyrimethamine Rifamopin(-) DNA-dependent RNA polymeraseSulfonamides(-) dihydropteroate synthetaseTrimethoprim(-) dihydrofolic acid reductase Amphotericin B Colistin Nyst

17、atin Polymyxins Phosphatidyl ethanolamine Ergosterol Chlorramphenicol (50S)Eythromycins (50S)Lincomycins (50S)Tetracyclines (30S)Aminoglycosides (30S) Bacitracin Cephalosporins Cycloserine Penicillins Vansomycin药理学南开大学第三十五章抗微生物药物概论HEREAntimicrobial mechanisms药理学南开大学第三十五章抗微生物药物概论HEREAntimicrobial mec

18、hanisms药理学南开大学第三十五章抗微生物药物概论Antimicrobial Agent IntroductionDefinitions and CharacteristicsAntimicrobial mechanismsResistance to antimicrobial drugs药理学南开大学第三十五章抗微生物药物概论HEREResistance to antimicrobial drugsClassification of drug resistance Mechanisms of drug resistanceOrigin of drug resistanceCross-re

19、sistance Intrinsic resistance Acquired resistance药理学南开大学第三十五章抗微生物药物概论HEREResistance to antimicrobial drugs Mechanisms of drug resistanceThere are many different mechanisms by which microorganisms might exhibit resistance to drugs. The following are fairly well supported by evidence:药理学南开大学第三十五章抗微生物药

20、物概论HEREResistance to antimicrobial drugs Mechanisms of drug resistance5-1. Microorganisms produce enzymes that destroy the active drugs 5-2. Microorganisms change their permeability to the drug 5-3. Microorganisms develop an altered structural target for the drug e.g. Staphylococci resistant to peni

21、cillin G: produce a beta-lactamase penicillinases that destroys the drug. G- bacteria resistant to aminoglycosides: produce adenylylating, phosphorylating or acetylating enzymes that destroy the drug.e.g. Tetracyclines accumulate in susceptible bacteria but not in resistant ones. Polymyxins resistan

22、t to it is probably associated with a change in permeability to the drugs. e.g. Chromosomal resistance to aminoglycosides is associated with the loss or alteration of a specific protein on the 30S subunit of the bacterial ribosome that serves as a receptor in susceptible organisms. Erythromycin resi

23、stant organisms have altered receptor site on the 50S subunit of the bacterial ribosome, resulting from methylation of a 23S ribosomal RNA.药理学南开大学第三十五章抗微生物药物概论HEREResistance to antimicrobial drugs Mechanisms of drug resistance5-4. Microorganisms develop an altered metabolic pathway that bypass react

24、ion inhibited by the drug 5-5. Microorganisms develop an altered enzyme that can still perform its metabolic function but is much less affected by the drug than the enzyme in the susceptible organism e.g. some sulfonamide-resistant bacteria dont require extracellular PABA, but like mammalian cells c

25、an utilize preformed folic acid. e.g. in some sulfonamide-susceptible bacteria, dihydropteroate synthetase has a much higher affinity for sulfonamide than for PABA. In sulfonamide-resistant mutants, the opposite is the case. 药理学南开大学第三十五章抗微生物药物概论HEREResistance to antimicrobial drugs Mechanisms of drug resistanceAll antimicrobial resistances involve a change in the genetic composition of the bacteria induced by such mechanisms as mutation, transduction, transformation and conjugation. 药理学南开大学第三十五章抗微生物药物概论HEREResistance to antimic