人工合成抗菌药PPT.ppt
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1、 Synthetic antimicrobial agents(人工合成人工合成(rn(rn nn h chn h chn)抗菌药抗菌药)Huifang Tang 第一页,共五十四页。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(硝基硝基(xio j)呋喃类呋喃类),etc.第二页,共五十四页。General fea
2、turesBroad 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.QuinolonesQuinolones 第三页,共五十四页。ChemistryDerived from basic structure of na
3、lidixic acid(萘萘啶酸啶酸)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.QuinolonesQuinolones 第四页,共五十四页。Chemical structureQuinolones(诺氟沙星诺氟沙星诺氟沙星诺氟沙星)(环丙沙星环丙沙星环丙沙星环丙沙星)(萘啶酸萘啶酸萘啶酸萘啶酸)Quinolones 第五页,共五十
4、四页。Generation Examples1 st(1962-1969)Nalidixic acid,萘啶酸萘啶酸2 nd(1969-1979)Pipemidic acid 吡哌酸吡哌酸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
5、 加替沙星加替沙星Moxifloxacin 莫西沙星莫西沙星ClassificationQuinolones 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,萘啶酸萘啶酸 The first generation drug of the quinolone antibioticsThe fi
6、rst generation drug of the quinolone antibiotics Moderate gram-negative activity and minimal systemic Moderate gram-negative activity and minimal systemic distributiondistributionClinical applications Clinical applications Uncomplicated urinary tract infections Uncomplicated urinary tract infections
7、QuinolonesQuinolones 第九页,共五十四页。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 Expanded gram-negative activity and atypical pathogen coverage,but limited gram-positive activity.coverage,but limited gram-positive act
8、ivity.Most active against aerobic gram-negative bacilliMost active against aerobic gram-negative bacilli Ciprofloxacin remains the quinolone most active against Ciprofloxacin remains the quinolone most active against Pseudomonas aeruginosaPseudomonas aeruginosaQuinolonesQuinolones 第十页,共五十四页。Second-g
9、eneration quinolones(1969-1979)Active against gram-positive and gram-negative bacteria,mycobacteria,mycoplasma支原体支原体支原体支原体and and legionella specieslegionella species军团军团军团军团(jntun)(jntun)杆菌属杆菌属杆菌属杆菌属.Longer half-lives due to slow elimination,Longer half-lives due to slow elimination,distribution in
10、to many tissues and body fluids and distribution into many tissues and body fluids and penetration into human cells.penetration into human cells.QuinolonesQuinolones 第十一页,共五十四页。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
11、星,Sparfloxacin 司帕沙星司帕沙星Added potency against gram-negative bacteria,Added potency against gram-negative bacteria,anaerobes and mycobacteria.anaerobes and mycobacteria.Retain expanded gram-negative and atypical Retain expanded gram-negative and atypical intracellular activity but have improved gram-i
12、ntracellular activity but have improved gram-positive coveragepositive coverageQuinolonesQuinolones 第十二页,共五十四页。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-Improve gram-positiv
13、e coverage,maintain gram-negative coverage,and gain anaerobic coverage.negative coverage,and gain anaerobic coverage.QuinolonesQuinolones 第十三页,共五十四页。Antimicrobial activity&spectrum(1)Bactericidal and have significant PAE.(1)Bactericidal and have significant PAE.(2)Excellent activity against aerobic
14、gram-negative bacteria,some agents have activity against Pesudomonas.(3)Several newer agents with improved activity against aerobic gram-positive bacteria.QuinolonesQuinolones 第十四页,共五十四页。Antimicrobial activity&spectrum(4)They also are effective against Chlamydia spp.(4)They also are effective agains
15、t Chlamydia spp.(衣原体)(衣原体)(衣原体)(衣原体),Legionella pneumophila(,Legionella pneumophila(军团菌军团菌军团菌军团菌),anaerobic bacteria,mycobacteria(,anaerobic bacteria,mycobacteria(分枝杆菌分枝杆菌分枝杆菌分枝杆菌).).(5)(5)Some Some agents agents have have limited limited activity activity against against multiple-resistance strains
16、.multiple-resistance strains.(6 6)Bactericidal concentration bacteriostatic Bactericidal concentration bacteriostatic concentrationconcentrationQuinolonesQuinolones 第十五页,共五十四页。Mechanism of actions Topoisomerases:enzymes that control and modify enzymes that control and modify the topological states o
17、f DNA in cells.the topological states of DNA in cells.Topoisomerase ITopoisomerase I,III III catalyse merely the catalyse merely the relaxation of DNArelaxation of DNA Topoisomerase II Topoisomerase II(DNA gyraseDNA gyrase)catalyse the catalyse the supercoiling of DNAsupercoiling of DNATopoisomerase
18、 IVTopoisomerase IV involved in the separation involved in the separation process of the DNA daughter chains after process of the DNA daughter chains after chromosome duplication.chromosome duplication.QuinolonesQuinolones 第十六页,共五十四页。Mechanism of actions The quinolone antibiotics target bacterial Th
19、e quinolone antibiotics target bacterial DNA gyrase(gram-negative bacteria)DNA gyrase(gram-negative bacteria)Topoisomerase IV(gram-positive bacteria).QuinolonesQuinolones 第十七页,共五十四页。Topoisomerase IV:involved in the separation process of Topoisomerase IV:involved in the separation process of the DNA
20、daughter chains after chromosome duplication.the DNA daughter chains after chromosome duplication.unable to catalyse the supercoiling of DNA,merely its unable to catalyse the supercoiling of DNA,merely its relaxation.relaxation.The enzyme comprises two subunits,ParC and ParE.The enzyme comprises two
21、 subunits,ParC and ParE.The ParC protein is homologous to the gyrase A protein,The ParC protein is homologous to the gyrase A protein,while the ParE subunit is homologous to the gyrase B while the ParE subunit is homologous to the gyrase B protein.protein.Mechanism of actionQuinolones 第十八页,共五十四页。Inh
22、ibition of topoisomerase IV Inhibition of topoisomerase IV interferes with interferes with separation of replicated chromosomal DNA into the separation of replicated chromosomal DNA into the respective daughter cells during cell division.respective daughter cells during cell division.Inhibition of D
23、NA gyrase Inhibition of DNA gyrase prevents the relaxation of positively prevents the relaxation of positively supercoiled DNA that is required for normal transcription and supercoiled DNA that is required for normal transcription and replicationreplication.Mechanism of actionQuinolones 第十九页,共五十四页。I
24、ntrinsic resistance is rareWith a frequency of about one in 107109,especially among staphylococci,pseudomonas,and serratia(沙雷氏菌沙雷氏菌).Resistance MechanismQuinolones 第二十页,共五十四页。(1)Mutation of the gyrA genethe gyrA gene that encoded the A subunit polypeptide can confer resistance to these drugs.(2)Muta
25、tion of the gene cfxB and nfxB that encoded the porin decreased permeability of cell membrance.(3)The high expression of(3)The high expression of norA genenorA gene(encoded active pump protein)increased drugs efflex by a active transport protein pump.(4)Plasmid mediated resistance.(4)Plasmid mediate
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