藥理學(xué)ppt課件南開大學(xué)第三十五章抗微生物藥物概論

1、Antimicrobial Agents——General Considerations,Medical school of Nankai UniversityJingling zhang and Jing Li,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。,Antimicrobial Agents,內(nèi)容化學(xué)

2、治療的涵義，藥物、宿主和致病病原體三者的相互關(guān)系。抗菌藥的創(chuàng)立及其發(fā)展簡史?？咕幍某Ｓ眯g(shù)語：抗菌譜、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。,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

3、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。,Introduction,Chemotherapeutic 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 i

4、nfectious organism but innocuous for the host.,Introduction,,Anti-infective agents are chemical substances that can kill or suppress the growth of microorganisms. Antibiotics are soluble compounds that are derived from

5、certain microorganisms and that inhibit the growth of other microorganisms.,The term antibiotics include synthetic antibacterial agents, such as the sulfonamides and quinolones, which are not products of microbes.,

6、Introduction,The major groups of antibacterial agents include:Sulfonamides Penicillins and Cephlosporines (betalactams) Aminoglycosides Tetracyclines and Chloramphrnicol Erythromycin, Clindamycin and Vancomycin, etc

7、.,Definitions and Characteristics,,Selective toxicityRelative selective toxicity Bacteriostatics BactericidalsChemotherapeutic index,Antimicrobial activityAntibiotic spectrum MICMBCPAE,It implies that the drug i

8、s 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 concentration that can be tolerated by the ho

9、st.,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 bactericidaldr

10、ugs are the ?-lactams & theaminoglycosides.,The effect isreversible: when thedrug is removed, theorganism will resumegrowth & infection ordisease may recur. The typicalbacteriostatic drugsare the sul

11、fonamides& tetracyclines.,Chemotherapeutic index:,The terms bacteristatics and bactericidal are relative, not absolute. Sometimes prolonged treatment with bacteriostatic drugs can kill certain microbial popul

12、ations (eg. Chloramphenicol and meningcocci), whereas bactericidal drugs may fail to do so (eg. penicillin G and enterococci), both in vitro and in vivo.,Definitions and Characteristics,,Selective toxicityRelativ

13、e selective toxicity Bacteriostatics BactericidalsChemotherapeutic index,Antimicrobial activityAntibiotic spectrum MICMBCPAE,It is the ability of antimicrobial agent inhibiting or killing microorganisms.,It is

14、the antimicrobial range of antibacterial agent. (narrow, broad),MIC： Minimum inhibitory concentration MBC： Minimum bactericidal concentration,PAE (postantibiotic effect ) It is a r

15、esidual bactericidal activity persisting after the serum concentration has fallen below the minimum inhibitory concentration.,Definitions and Characteristics,,The effectiveness of antimicrobial agents usually relie

16、s 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

17、 of activity (Antimicrobial Activity) Therapeutic uses Untoward effects,Antimicrobial mechanisms,,For a majority of antimicrobial drugs, the mechanism of action is not completely understood. However, for purposes o

18、f discussion, it is convenient to present antimicrobial mechanisms under 4 distinct headings:,Inhibition of cell wall synthesisAlteration in the permeability of cell membrane or active transport across cell membraneInh

19、ibition of protein synthesis (ie. inhibition of translation and transcription of genetic material)Inhibition of nucleic acid synthesis,Antimicrobial mechanisms,Quinolones →Block action of DNA gyrase

20、Pyrimethamine Rifamopin→(-) DNA-dependent RNA polymeraseSulfonamides→(-) dihydropteroate synthetaseTrimethoprim→(-) dihydrofolic acid reductas

21、e,Amphotericin B Colistin Nystatin Polymyxins Phosphatidyl ethanolamine Ergosterol,,Antimicrobial mechanisms,,,Antimicrobial mechanisms,,Resistance to antimicrobial drugs,,Classification of drug resistance

22、 Mechanisms of drug resistanceOrigin of drug resistanceCross-resistance,Intrinsic resistance Acquired resistance,Resistance to antimicrobial drugs —— Mechanisms of drug resistance,There are many d

23、ifferent mechanisms by which microorganisms might exhibit resistance to drugs. The following are fairly well supported by evidence:,Resistance to antimicrobial drugs —— Mechanisms of drug resistance,5-1. Microorganis

24、ms 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. ⑴ Staphylococci resistant to penicil

25、lin G: produce a beta-lactamase → penicillinases that destroys the drug.⑵ G- bacteria resistant to aminoglycosides: produce adenylylating, phosphorylating or acetylating enzymes that destroy the drug.,e.g. Tetracycl

26、ines accumulate in susceptible bacteria but not in resistant ones. Polymyxins resistant to it is probably associated with a change in permeability to the drugs.,e.g. ⑴Chromosomal resistance to aminoglycosides is assoc

27、iated 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. ⑵Erythromycin resistant organisms have altered receptor site

28、 on the 50S subunit of the bacterial ribosome, resulting from methylation of a 23S ribosomal RNA.,Resistance to antimicrobial drugs —— Mechanisms of drug resistance,5-4. Microorganisms develop an altered metabolic

29、 pathway that bypass reaction 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 or

30、ganism,e.g. some sulfonamide-resistant bacteria don’t require extracellular PABA, but like mammalian cells can utilize preformed folic acid.,e.g. in some sulfonamide-susceptible bacteria, dihydropteroate synthe

31、tase has a much higher affinity for sulfonamide than for PABA. In sulfonamide-resistant mutants, the opposite is the case.,Resistance to antimicrobial drugs —— Mechanisms of drug resistance,,All antimicrobial resis

32、tances involve a change in the genetic composition of the bacteria induced by such mechanisms as mutation, transduction, transformation and conjugation.,Resistance to antimicrobial drugs —— Origin of drug resistance,,

33、Resistance may be genetic or nongenetic:⑴ Nongenetic origin⑵ Genetic origin ① Chromosomal determinants ② Extrachromosomal determinants,Plasmids are extrachromosomal genetic elements, such as: R factors.,Mutat

34、ions,,The transfer of resistance genes between genetic elements within the bacterium ① Transposons ② Gene cassettes and integrons,Resistance to antimicrobial drugs —— Origin of drug resistance,,The transfer of resis

35、tance genes between bacteria① Conjugation② Transduction ③ Transformation ④ Translocation or transposition,Resistance to antimicrobial drugs —— Origin of drug resistance,Resistance to antimicrobial drugs,,Classific