1、Antimicrobial Agents General Considerations,Medical school of Nankai University Jingling zhang and Jing Li,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。,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、耐药性和化疗指数的概念及其意义。细菌的结构及其功能。,Antimic
2、robial 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。,Introduction,Chemotherapeutic agents are chemicals (either natural or synthetic) used to inhibit the growth of malignant or canc
3、erous cells within the body & to be toxic for the infectious 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 certain microorganisms and that
4、 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.,Introduction,The major groups of antibacterial agents include: Sulfonamides Penicillins and Cephlosporines (betalacta
5、ms) Aminoglycosides Tetracyclines and Chloramphrnicol Erythromycin, Clindamycin and Vancomycin, etc.,Definitions and Characteristics,Selective toxicity Relative selective toxicity Bacteriostatics Bactericidals Chemotherapeutic index,Antimicrobial activity Antibiotic spectrum MIC MBC PAE,It implies t
6、hat thedrug is harmful toa parasite withoutbeing harmful tothe host. An idealantimicrobial drugexhibits selectivetoxicity.,It means that adrug may damagea parasite in aconcentration thatcan be toleratedby the host.,This term describesa drug thattemporarily inhibitsthe growth of amicroorganism.,The t
7、erm describes a drug that attaches to its receptor & causes the death of the microorganism.Typical bactericidal drugs are the -lactams & the aminoglycosides.,The effect is reversible: when the drug is removed, the organism will resume growth & infection or disease may recur.The typical bacteriostati
8、c drugs are the sulfonamides & tetracyclines.,Chemotherapeuticindex:,The terms bacteristatics and bactericidal are relative, not absolute. Sometimes prolonged treatment with bacteriostatic drugs can kill certain microbial populations (eg. Chloramphenicol and meningcocci), whereas bactericidal drugs
9、may fail to do so (eg. penicillin G and enterococci), bothin vitro and in vivo.,Definitions and Characteristics,Selective toxicity Relative selective toxicity Bacteriostatics Bactericidals Chemotherapeutic index,Antimicrobial activity Antibiotic spectrum MIC MBC PAE,It is the ability of antimicrobia
10、l agent inhibiting or killing microorganisms.,It is the antimicrobial range of antibacterial agent. (narrow, broad),MIC：MinimuminhibitoryconcentrationMBC： Minimumbactericidalconcentration,PAE (postantibiotic effect )It is a residual bactericidal activity persisting after the serum concentration has
11、fallen below the minimum inhibitory concentration.,Definitions and Characteristics,The effectiveness of antimicrobial agents usually relies on a biochemical or physiologic difference between the host and the parasite. Antimicrobial drugs can differ from one another in the following ways:,Chemical pr
12、opertiesMechanism of actionPharmocokineticsSpectrum of activity (Antimicrobial Activity)Therapeutic usesUntoward effects,Antimicrobial mechanisms,For a majority of antimicrobial drugs, the mechanism of action is not completely understood. However, for purposes of discussion, it is convenient to pres
13、ent antimicrobial mechanisms under 4 distinct headings:,Inhibition of cell wall synthesis Alteration in the permeability of cell membrane or active transport across cell membrane Inhibition of protein synthesis (ie. inhibition of translation and transcription of genetic material) Inhibition of nucle
14、ic acid synthesis,Antimicrobial mechanisms,Quinolones Block action of DNAgyrase Pyrimethamine Rifamopin(-) DNA-dependentRNA polymerase Sulfonamides(-) dihydropteroate synthetase Trimethoprim(-) dihydrofolicacid reductase,Amphotericin BColistin NystatinPolymyxinsPhosphatidylethanolamineErgosterol,Ant
15、imicrobial mechanisms,Antimicrobial mechanisms,Resistance to antimicrobial drugs,Classification of drug resistance Mechanisms of drug resistance Origin of drug resistance Cross-resistance,Intrinsic resistanceAcquired resistance,Resistance to antimicrobial drugs Mechanisms of drug resistance,There ar
16、e many different 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. Microorganisms produce enzymes that destroy the active drugs 5-2. Microorganisms change the
17、ir permeability to the drug 5-3. Microorganisms develop an altered structural target for the drug,e.g. Staphylococci resistant to penicillin G: produce a beta-lactamase penicillinases that destroys the drug. G- bacteria resistant to aminoglycosides: produce adenylylating, phosphorylating or acetylat
18、ing enzymes that destroy the drug.,e.g. Tetracyclines 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. Chromosomal resistance to aminoglycosides is associated with the loss or alteration o
19、f a specific protein on the 30S subunit of the bacterial ribosome that serves as a receptor in susceptible organisms.Erythromycin resistant organisms have altered receptor site on the 50S subunit of the bacterial ribosome, resulting from methylation of a 23S ribosomal RNA.,Resistance to antimicrobia
20、l drugs Mechanisms of drug resistance,5-4. Microorganisms develop an altered metabolic 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 susceptib
21、le organism,e.g. some sulfonamide-resistant bacteria dont require extracellular PABA, but like mammalian cells can 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-resistan
22、t mutants, the opposite is the case.,Resistance to antimicrobial drugs Mechanisms of drug resistance,All antimicrobial resistances involve a change in the genetic composition of the bacteria induced by such mechanisms as mutation, transduction, transformation and conjugation.,Resistance to antimicro
23、bial drugs Origin of drug resistance,Resistance may be genetic or nongenetic: Nongenetic origin Genetic origin Chromosomal determinants Extrachromosomal determinants,Plasmids are extrachromosomal genetic elements, such as: R factors.,Mutations,The transfer of resistance genes between genetic element
24、s within the bacterium Transposons Gene cassettes and integrons,Resistance to antimicrobial drugs Origin of drug resistance,The transfer of resistance genes between bacteria Conjugation Transduction Transformation Translocation or transposition,Resistance to antimicrobial drugs Origin of drug resistance,Resistance to antimicrobial drugs,Classification of drug resistance Mechanisms of drug resistance Origin of drug resistance Cross-resistance,THANK YOU,
