2022年医学专题—人工合成抗菌药PPT.ppt

Synthetic antimicrobial agents(人工合成(rn n h chn)抗菌药),Huifang Tang,第一页，共五十四页。,Classification of Synthetic antimicrobial agents,.Quinolones(喹诺酮类);.Sulfonamides(磺胺类);.Other synthetic antimicrobial agents:Trimethoprim(甲氧苄啶)Nitrofurans(硝基(xio j)呋喃类),etc.,第二页，共五十四页。,General featuresBroad antimicrobial activity and are effective after oral administration for the treatment of a wide variety of infectious disease.Relatively few side effects.Microbial resistance to their action does not develop rapidly.,Quinolones,Quinolones,第三页，共五十四页。,ChemistryDerived from basic structure of nalidixic acid(萘啶酸)and have substituents at N-1,C-5,C-7,position 8 and a fluorine atom at position 6.Fluorine at position 6 enhances gyrase inhibition and cell penetration.,Quinolones,Quinolones,第四页，共五十四页。,Chemical structure,Quinolones,(诺氟沙星),(环丙沙星),(萘啶酸),Quinolones,第五页，共五十四页。,Generation Examples1 st(1962-1969)Nalidixic acid,萘啶酸2 nd(1969-1979)Pipemidic acid 吡哌酸Cinoxacin 西诺沙星3 rd(1980-1996)Norfloxacin 诺氟沙星 Levofloxacin 左氧氟沙星 Ciprofloxacin 环丙沙星Ofloxacin 氧氟沙星sparfloxacin 司帕沙星4 th(1997-)Grepafloxacin 格帕沙星Clinafloxacin 克林沙星Gatifloxacin 加替沙星Moxifloxacin 莫西沙星,Classification,Quinolones,第六页，共五十四页。,Summary of antimicrobial spectrum of quinolones.,第七页，共五十四页。,Typical therapeutic applications of uoroquinolones.,第八页，共五十四页。,First-generation agents(1962-1969)Nalidixic acid,萘啶酸The first generation drug of the quinolone antibiotics Moderate gram-negative activity and minimal systemic distributionClinical applications Uncomplicated urinary tract infections,Quinolones,Quinolones,第九页，共五十四页。,Second-generation quinolones(1969-1979)Pipemidic acid 吡哌酸 Cinoxacin西诺沙星Expanded gram-negative activity and atypical pathogen coverage,but limited gram-positive activity.Most active against aerobic gram-negative bacilliCiprofloxacin remains the quinolone most active against Pseudomonas aeruginosa,Quinolones,Quinolones,第十页，共五十四页。,Second-generation quinolones(1969-1979)Active against gram-positive and gram-negative bacteria,mycobacteria,mycoplasma支原体and legionella species军团(jntun)杆菌属.Longer half-lives due to slow elimination,distribution into many tissues and body fluids and penetration into human cells.,Quinolones,Quinolones,第十一页，共五十四页。,Third-generation quinolones(1980-1996)Norfloxacin 诺氟沙星，Levofloxacin 左氧氟沙星，Ciprofloxacin 环丙沙星，Ofloxacin 氧氟沙星，Sparfloxacin 司帕沙星Added potency against gram-negative bacteria,anaerobes and mycobacteria.Retain expanded gram-negative and atypical intracellular activity but have improved gram-positive coverage,Quinolones,Quinolones,第十二页，共五十四页。,Fourth-generation agents(1997-)Grepafloxacin 格帕沙星，Clinafloxacin 克林沙星，Gatifloxacin 加替沙星，Moxifloxacin 莫西沙星Improve gram-positive coverage,maintain gram-negative coverage,and gain anaerobic coverage.,Quinolones,Quinolones,第十三页，共五十四页。,Antimicrobial activity&spectrum(1)Bactericidal and have significant PAE.(2)Excellent activity against aerobic gram-negative bacteria,some agents have activity against Pesudomonas.(3)Several newer agents with improved activity against aerobic gram-positive bacteria.,Quinolones,Quinolones,第十四页，共五十四页。,Antimicrobial activity&spectrum(4)They also are effective against Chlamydia spp.（衣原体）,Legionella pneumophila(军团菌),anaerobic bacteria,mycobacteria(分枝杆菌).(5)Some agents have limited activity against multiple-resistance strains.（6）Bactericidal concentration bacteriostatic concentration,Quinolones,Quinolones,第十五页，共五十四页。,Mechanism of actions Topoisomerases:enzymes that control and modify the topological states of DNA in cells.Topoisomerase I，III catalyse merely the relaxation of DNATopoisomerase II（DNA gyrase）catalyse the supercoiling of DNATopoisomerase IV involved in the separation process of the DNA daughter chains after chromosome duplication.,Quinolones,Quinolones,第十六页，共五十四页。,Mechanism of actions The quinolone antibiotics target bacterial DNA gyrase(gram-negative bacteria)Topoisomerase IV(gram-positive bacteria).,Quinolones,Quinolones,第十七页，共五十四页。,Topoisomerase IV:involved in the separation process of the DNA daughter chains after chromosome duplication.unable to catalyse the supercoiling of DNA,merely its relaxation.The enzyme comprises two subunits,ParC and ParE.The ParC protein is homologous to the gyrase A protein,while the ParE subunit is homologous to the gyrase B protein.,Mechanism of action,Quinolones,第十八页，共五十四页。,Inhibition of topoisomerase IV interferes with separation of replicated chromosomal DNA into the respective daughter cells during cell division.,Inhibition of DNA gyrase prevents the relaxation of positively supercoiled DNA that is required for normal transcription and replication.,Mechanism of action,Quinolones,第十九页，共五十四页。,Intrinsic resistance is rareWith a frequency of about one in 107109,especially among staphylococci,pseudomonas,and serratia(沙雷氏菌).,Resistance Mechanism,Quinolones,第二十页，共五十四页。,(1)Mutation of the gyrA gene that encoded the A subunit polypeptide can confer resistance to these drugs.(2)Mutation of the gene cfxB and nfxB that encoded the porin decreased permeability of