藥理學(xué)南開大學(xué)第三十五章抗微生物藥物概論

1、Antimicrobial AgentsGeneral Considerations Medical school of Nankai UniversityJingling zhang and Jing Li藥理學(xué)南開大學(xué)第三十五章抗微生物藥物概論Antimicrobial Agents目的 了解化學(xué)治療的含義及抗菌藥的發(fā)展簡史。掌握有關(guān)抗菌藥物的常用術(shù)語和各類抗菌藥物的抗菌作用原理，細菌耐藥性產(chǎn)生的機制。藥理學(xué)南開大學(xué)第三十五章抗微生物藥物概論Antimicrobial Agents內(nèi)容化學(xué)治療的涵義，藥物、宿主和致病病原體三者的相互關(guān)系?？咕幍膭?chuàng)立及其發(fā)展簡史?？咕幍某Ｓ眯g(shù)語：抗菌譜、

2、耐藥性和化療指數(shù)的概念及其意義。細菌的結(jié)構(gòu)及其功能。藥理學(xué)南開大學(xué)第三十五章抗微生物藥物概論Antimicrobial Agents常用抗菌藥的作用原理：抑制細菌葉酸代謝：磺胺藥及其增效劑。影響細菌細胞壁的合成：青霉素及頭孢霉素。影響細菌蛋白質(zhì)的合成：鏈霉素、紅霉素、四環(huán)素類和氯霉素。影響細菌細胞漿膜的功能：多粘菌素、制霉菌素和二性霉素B。細菌耐藥性產(chǎn)生的機制：合成破壞抗生素的酶，改變細胞膜的通透性，改變藥物作用的靶結(jié)構(gòu)，改變細菌的代謝途徑。藥理學(xué)南開大學(xué)第三十五章抗微生物藥物概論Antimicrobial Agent IntroductionDefinitions and Character

3、isticsAntimicrobial mechanismsResistance to antimicrobial drugs藥理學(xué)南開大學(xué)第三十五章抗微生物藥物概論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.藥理學(xué)南開大學(xué)第三十五章抗微生物藥物概論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.藥理學(xué)南開大學(xué)第三十五章抗微生物藥物概論HEREIntroductionThe major groups of antibacterial agents include:Sulfonamides Penicillins and Cephlosporines (betalactams) Aminoglycosides Tetracyclines and Chlor

6、amphrnicol Erythromycin, Clindamycin and Vancomycin, etc. 藥理學(xué)南開大學(xué)第三十五章抗微生物藥物概論Antimicrobial Agent IntroductionDefinitions and CharacteristicsAntimicrobial mechanismsResistance to antimicrobial drugs藥理學(xué)南開大學(xué)第三十五章抗微生物藥物概論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.藥理學(xué)南開大學(xué)第三十五章抗微生物藥物概論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. 藥理學(xué)南開大學(xué)第三十五章抗微生物藥物概論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藥理學(xué)南開大學(xué)第三

14、十五章抗微生物藥物概論Antimicrobial Agent IntroductionDefinitions and CharacteristicsAntimicrobial mechanismsResistance to antimicrobial drugs藥理學(xué)南開大學(xué)第三十五章抗微生物藥物概論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:藥理學(xué)南開大學(xué)第三十五章抗微生物藥物概論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藥理學(xué)南開大學(xué)第三十五章抗微生物藥物概論HEREAntimicrobial mechanisms藥理學(xué)南開大學(xué)第三十五章抗微生物藥物概論HEREAntimicrobial mec

18、hanisms藥理學(xué)南開大學(xué)第三十五章抗微生物藥物概論Antimicrobial Agent IntroductionDefinitions and CharacteristicsAntimicrobial mechanismsResistance to antimicrobial drugs藥理學(xué)南開大學(xué)第三十五章抗微生物藥物概論HEREResistance to antimicrobial drugsClassification of drug resistance Mechanisms of drug resistanceOrigin of drug resistanceCross-re

19、sistance Intrinsic resistance Acquired resistance藥理學(xué)南開大學(xué)第三十五章抗微生物藥物概論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:藥理學(xué)南開大學(xué)第三十五章抗微生物藥

20、物概論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.藥理學(xué)南開大學(xué)第三十五章抗微生物藥物概論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. 藥理學(xué)南開大學(xué)第三十五章抗微生物藥物概論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. 藥理學(xué)南開大學(xué)第三十五章抗微生物藥物概論HEREResistance to antimic