1、 Synthetic antimicrobial agents(人工合成抗菌药人工合成抗菌药)Huifang Tang Classification of Synthetic antimicrobial agents .Quinolones(喹诺酮类喹诺酮类);.Sulfonamides(磺胺类磺胺类);.Other synthetic antimicrobial agents:Trimethoprim(甲氧苄啶甲氧苄啶)Nitrofurans(硝基呋喃类硝基呋喃类),etc.General features Broad antimicrobial activity and are effec
2、tive 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 Chemistry Derived from basic structure of nalidixic acid(萘啶酸萘啶酸)and have substituents at N-1,C-5,C-
3、7,position 8 and a fluorine atom at position 6.Fluorine at position 6 enhances gyrase inhibition and cell penetration.Quinolones Quinolones Chemical structure Quinolones(诺氟沙星诺氟沙星)(环丙沙星环丙沙星)(萘啶酸萘啶酸)Quinolones Generation Examples 1 st(1962-1969)Nalidixic acid,萘啶酸萘啶酸 2 nd(1969-1979)Pipemidic acid 吡哌酸吡哌
4、酸 Cinoxacin 西诺沙星西诺沙星 3 rd(1980-1996)Norfloxacin 诺氟沙星诺氟沙星 Levofloxacin 左氧氟沙星左氧氟沙星 Ciprofloxacin 环丙沙星环丙沙星 Ofloxacin 氧氟沙星氧氟沙星 sparfloxacin 司帕沙星司帕沙星 4 th(1997-)Grepafloxacin 格帕沙星格帕沙星 Clinafloxacin 克林沙星克林沙星 Gatifloxacin 加替沙星加替沙星 Moxifloxacin 莫西沙星莫西沙星 Classification Quinolones Summary of antimicrobial spe
5、ctrum of quinolones.Typical therapeutic applications of?uoroquinolones.First-generation agents(1962-1969)Nalidixic acid,萘啶酸萘啶酸 The first generation drug of the quinolone antibiotics Moderate gram-negative activity and minimal systemic distribution Clinical applications Uncomplicated urinary tract in
6、fections Quinolones Quinolones Second-generation quinolones(1969-1979)Pipemidic acid 吡哌酸吡哌酸 Cinoxacin西诺沙星西诺沙星 Expanded gram-negative activity and atypical pathogen coverage,but limited gram-positive activity.Most active against aerobic gram-negative bacilli Ciprofloxacin remains the quinolone most a
7、ctive against Pseudomonas aeruginosa Quinolones Quinolones Second-generation quinolones(1969-1979)Active against gram-positive and gram-negative bacteria,mycobacteria,mycoplasma支支原体原体and legionella species军团杆菌属军团杆菌属.Longer half-lives due to slow elimination,distribution into many tissues and body fl
8、uids and penetration into human cells.Quinolones Quinolones Third-generation quinolones(1980-1996)Norfloxacin 诺氟沙星诺氟沙星，Levofloxacin 左氧氟沙星左氧氟沙星，Ciprofloxacin 环丙沙星环丙沙星，Ofloxacin 氧氟沙星氧氟沙星，Sparfloxacin 司帕沙星司帕沙星 Added potency against gram-negative bacteria,anaerobes and mycobacteria.Retain expanded gram-
9、negative and atypical intracellular activity but have improved gram-positive coverage Quinolones Quinolones Fourth-generation agents(1997-)Grepafloxacin 格帕沙星，格帕沙星，Clinafloxacin 克林沙星，克林沙星，Gatifloxacin 加替沙星，加替沙星，Moxifloxacin 莫西沙星莫西沙星 Improve gram-positive coverage,maintain gram-negative coverage,and g
10、ain anaerobic coverage.Quinolones Quinolones 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
11、 bacteria.Quinolones Quinolones Antimicrobial activity&spectrum(4)They also are effective against Chlamydia spp.（衣原体）（衣原体）,Legionella pneumophila(军团军团菌菌),anaerobic bacteria,mycobacteria(分枝杆分枝杆菌菌).(5)Some agents have limited activity against multiple-resistance strains.（6）Bactericidal concentration b
12、acteriostatic concentration Quinolones Quinolones Mechanism of actions Topoisomerases:enzymes that control and modify the topological states of DNA in cells.Topoisomerase I，III catalyse merely the relaxation of DNA Topoisomerase II（DNA gyrase）catalyse the supercoiling of DNA Topoisomerase IV involve
13、d in the separation process of the DNA daughter chains after chromosome duplication.Quinolones Quinolones Mechanism of actions The quinolone antibiotics target bacterial DNA gyrase(gram-negative bacteria)Topoisomerase IV(gram-positive bacteria).Quinolones Quinolones Topoisomerase IV:involved in the
14、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 prot
15、ein.Mechanism of action Quinolones 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
16、and replication.Mechanism of action Quinolones Intrinsic resistance is rare With a frequency of about one in 107109,especially among staphylococci,pseudomonas,and serratia(沙雷氏菌沙雷氏菌).Resistance Mechanism Quinolones (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 cell membrance.(3)The high expression of norA gene(encoded active pump protein)increased drugs