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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 featuresBroad antimicrobial activity and
2、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 ChemistryDerived from basic structure of nalidixic acid (萘啶酸萘啶酸)and have substituents at
3、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 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 Generation Examples1 st (1962-1969) Nalidixic
4、 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 加替沙星加替沙星Moxifloxacin 莫西沙星莫西沙星Classific
5、ationQuinolones Summary of antimicrobial spectrum 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 antibioticsThe first generation drug of the quinolone antibiotics Moderate gram-neg
6、ative activity and minimal systemic Moderate gram-negative activity and minimal systemic distributiondistributionClinical applications Clinical applications Uncomplicated urinary tract infections Uncomplicated urinary tract infectionsQuinolonesQuinolones Second-generation quinolones (1969-1979) Pipe
7、midic 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 activity. Most active against aerobic gram-negative bacilliMost active aga
8、inst aerobic gram-negative bacilli Ciprofloxacin remains the quinolone most active against Ciprofloxacin remains the quinolone most active against Pseudomonas aeruginosaPseudomonas aeruginosaQuinolonesQuinolones Second-generation quinolones (1969-1979) Active against gram-positive and gram-Active ag
9、ainst gram-positive and gram-negative bacteria, mycobacteria, mycoplasmanegative bacteria, mycobacteria, mycoplasma支支支支原体原体原体原体and legionella speciesand legionella species军团杆菌属军团杆菌属军团杆菌属军团杆菌属. . Longer half-lives due to slow elimination, Longer half-lives due to slow elimination, distribution into m
10、any tissues and body fluids distribution into many tissues and body fluids and penetration into human cells. and penetration into human cells. QuinolonesQuinolones 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， Sparf
11、loxacin 司帕沙星司帕沙星Added potency against gram-negative Added potency against gram-negative bacteria, anaerobes and mycobacteria. bacteria, anaerobes and mycobacteria. Retain expanded gram-negative and atypical Retain expanded gram-negative and atypical intracellular activity but have improved gram-intr
12、acellular activity but have improved gram-positive coveragepositive coverageQuinolonesQuinolones Fourth-generation agents (1997- ) Grepafloxacin Grepafloxacin 格帕沙星，格帕沙星，格帕沙星，格帕沙星，Clinafloxacin Clinafloxacin 克林沙星，克林沙星，克林沙星，克林沙星，Gatifloxacin Gatifloxacin 加替沙星，加替沙星，加替沙星，加替沙星，Moxifloxacin Moxifloxacin 莫
13、西沙星莫西沙星莫西沙星莫西沙星Improve gram-positive coverage, maintain Improve gram-positive coverage, maintain gram-negative coverage, and gain anaerobic gram-negative coverage, and gain anaerobic coverage.coverage.QuinolonesQuinolones Antimicrobial activity & spectrum(1) Bactericidal and have significant PAE. (1
14、) Bactericidal and have significant PAE. (2)Excellent (2)Excellent activity activity against against aerobic aerobic gram-gram-negative negative bacteria, bacteria, some some agents agents have have activity against Pesudomonas. activity against Pesudomonas. (3) (3) Several Several newer newer agent
15、s agents with with improved improved activity activity against against aerobic aerobic gram-positive gram-positive bacteria.bacteria.QuinolonesQuinolones Antimicrobial activity & spectrum(4) They also are effective against Chlamydia (4) They also are effective against Chlamydia spp.spp.（衣原体）（衣原体）（衣原
16、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.multiple-resistance
17、 strains.（6 6）Bactericidal concentration bacteriostatic Bactericidal concentration bacteriostatic concentrationconcentrationQuinolonesQuinolones Mechanism of actions Topoisomerases :Topoisomerases : enzymes that control and enzymes that control and modify the topological states of DNA in cells.modif
18、y the topological states of DNA in cells. Topoisomerase ITopoisomerase I， III III catalyse merely the catalyse merely the relaxation of DNArelaxation of DNATopoisomerase II Topoisomerase II （DNA gyraseDNA gyrase） catalyse catalyse the supercoiling of DNAthe supercoiling of DNATopoisomerase IVTopoiso
19、merase 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 Mechanism of actions The quinolone antibiotics target bacterial The quinolone antibioti
20、cs target bacterial DNA gyrase (gram-negative bacteria) DNA gyrase (gram-negative bacteria) Topoisomerase IV (gram- positive Topoisomerase IV (gram- positive bacteria).bacteria).QuinolonesQuinolones Topoisomerase IV : involved in the separation Topoisomerase IV : involved in the separation process o
21、f the DNA daughter chains after process of the DNA daughter chains after chromosome duplication.chromosome duplication. unable to catalyse the supercoiling of DNA, merely unable to catalyse the supercoiling of DNA, merely its relaxation. its relaxation. The enzyme comprises two subunits, ParC and Pa
22、rE.The enzyme comprises two subunits, ParC and ParE. The ParC protein is homologous to the gyrase A The ParC protein is homologous to the gyrase A protein, while the ParE subunit is homologous to the protein, while the ParE subunit is homologous to the gyrase B protein.gyrase B protein.Mechanism of
23、actionQuinolones Inhibition 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 divi
24、sion. Inhibition of DNA gyrase Inhibition of DNA gyrase prevents the relaxation prevents the relaxation of positively supercoiled DNA that is required for of positively supercoiled DNA that is required for normal transcription and replicationnormal transcription and replication. . Mechanism of actio
25、nQuinolones Intrinsic 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 (1) Mutation of the gyrA gene that encoded the A subunit polypeptide can confer resistance to these drugs.(2) Mutation o
26、f 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 efflex by a active transport protein pump.(4) Plasmid mediated resistance.Resistance MechanismQuinolones (1) Well absorbed afte
27、r oral administration.(2) Distributed widely in body tissue, even in CSF.(3) Excreted mainly in urine. Routes of elimination differ among the Quinolones. ADME of QuinolonesQuinolones (1)Urinary tract infections.The main indication for quinolones In the treatment of uncomplicated and complicated UTIs
28、, cure rates can exceed 90% and 80%, respectively.Potent agents to use against Haemophilus ducreyi (软性下疳嗜血杆菌软性下疳嗜血杆菌) and penicillin-sensitive and penicillin-resistant Neisseria gonorrhoeae淋淋(病双病双)球菌球菌. Clinical UsesQuinolones (2) GI and abdominal infections.(2) GI and abdominal infections.Excellent
29、 in vitro activity against many Excellent in vitro activity against many enteric pathogens, including Escherichia colienteric pathogens, including Escherichia coli大肠杆菌大肠杆菌大肠杆菌大肠杆菌, Aeromonas, Aeromonas气单胞菌属气单胞菌属气单胞菌属气单胞菌属, Shigella, Shigella志贺志贺(氏氏)杆菌杆菌, Salmonella, Salmonella沙门氏菌沙门氏菌, Campylobacter
30、, Campylobacter弯曲杆菌属弯曲杆菌属, Vibrio, Vibrio弧菌属弧菌属, and Yersinia , and Yersinia speciesspecies耶尔森菌耶尔森菌耶尔森菌耶尔森菌Furthermore, quinolone drug concentrations Furthermore, quinolone drug concentrations in feces are exceedingly high.in feces are exceedingly high. Clinical UsesQuinolones (3) Respiratory tract
31、infections. Have inferior activity against streptococciHave inferior activity against streptococci链球菌链球菌链球菌链球菌and and should not be used as primary therapy for common should not be used as primary therapy for common upper respiratory tract infections. upper respiratory tract infections. Alternatives
32、 for treatment of acute exacerbation Alternatives for treatment of acute exacerbation of chronic bronchitis in patients with obstructive of chronic bronchitis in patients with obstructive pulmonary disease who are intolerant of or have pulmonary disease who are intolerant of or have developed resist
33、ance to first-line antibiotics.developed resistance to first-line antibiotics. antibiotics with activity against Streptococcus antibiotics with activity against Streptococcus pneumoniae, Haemophilus influenzaepneumoniae, Haemophilus influenzae流感流感流感流感( (嗜血嗜血嗜血嗜血) )杆菌杆菌杆菌杆菌, , and Moraxella catarrhal
34、isand Moraxella catarrhalis粘膜炎莫拉菌粘膜炎莫拉菌粘膜炎莫拉菌粘膜炎莫拉菌. . (4) Other infections： Bone, joint and soft tissue infections.Clinical UsesQuinolones (1)Gastrointestinal effects.(1)Gastrointestinal effects. The most common reactions The most common reactions (2)CNS side effects.(2)CNS side effects. Penetrate
35、BBBPenetrate BBB GABA GABA (3)Allergic reaction.(3)Allergic reaction. Skin rashses, itchs, angioneuroedema , etc.Skin rashses, itchs, angioneuroedema , etc. PhotosensitivityPhotosensitivity(4)other effects.(4)other effects. Cardiac toxicityCardiac toxicity： Q-T interval Q-T interval Liver and renal
36、injuryLiver and renal injuryAdverse reactionsQuinolones (4)other effects.Muscle skeletal system Amyasthenia 肌无力肌无力, myosalgia肌痛肌痛, joint pain and inflammationIncrease intracranial pressure in infantsAdverse reactionsQuinolones Pipemidic acid (吡哌酸吡哌酸)Norfloxacin (诺氟沙星诺氟沙星)Ciprofloxacin (环丙杀星环丙杀星)Oflo
37、xacin（氧氟沙星）（氧氟沙星）Levofloxacin（左氧氟沙星）（左氧氟沙星）Lomefloxacin（洛美沙星）（洛美沙星）Fleroxacin（氟罗沙星）（氟罗沙星）Sparfloxacin（司帕沙星）（司帕沙星）Quinolones agentsQuinolones PharmacokineticPharmacokinetic PropertiesProperties ofof FluoroquinolonesFluoroquinolonesQuinolones 盐酸安妥沙星-我国第一个具有自主知识产权的沙星类抗菌药 盐酸安妥沙星与细菌作用2到4小时，即可杀灭99%以上细菌。在沙
38、星类药物安全性的重要指标光毒性方面，它的毒性明显低于现有主要产品洛美沙星、司帕沙星、氟罗沙星、环丙沙星。盐酸安妥沙星具有优异的药物代谢性质，与最新的第四代沙星类药物相比，它的口服剂量最低，每天只需服用1次，属长效抗菌药物。盐酸安妥沙星治疗呼吸道、泌尿道、皮肤软组织等三大系统细菌感染性疾病，疗效确切而不良反应少，总有效率超过95%。喹诺酮类研究两大动向 继续研发第四代氟喹诺酮近年上市的:吉米沙星(gemifloxacin ),巴洛沙星目前正在研发中的:西他沙星(sitafloxacin ),奥鲁沙星 (olamufloxacin )。 注意研究结构变幅更大的喹诺酮近年上市的帕珠沙星(pazufl
39、oxacin )、鲁利沙星(prulifloxacin )非氟喹诺酮格林沙星(garenoxacin ) SulfonamidesSulfonamidesSulfonamides (1) Sulfonamides have a wide range of antimicrobial activity.G+,G- bacteria, Nocardia 诺卡菌属诺卡菌属, Bedsonia trachomatis沙眼衣原体沙眼衣原体, etc.Enteric bacteria etc. less effectiveRicketts organism (2) Sulfonamides exert o
40、nly bacteriostatic effect.Antimicrobial activitySulfonamides Structural analogs and competitive antagonists of para-aminobenzoic acid (对氨基对氨基苯甲酸苯甲酸 PABA) Prevent normal bacterial utilization of PABA for the synthesis of folic acid. Mechanism of actionSulfonamides Mechanism of actionSulfonamides Orig
41、inate by random mutation and selection or by transfer of resistance by plasmaides. Such resistance usually is persistent and irreversible. Mechanism of ResistanceSulfonamides The resistance characterized by:(1)A lower affinity for sulfonamides by the dihydropteroate synthase(2)Decreased cell permeab
42、ility or active efflux of the drug(3)An alternative pathway to synthesis the essential metabolites(4)An increased production of essential metaboltesMechanism of ResistanceSulfonamides (1) Oral absorbable agentsShort-acting agentsMedium-acting agentsLong-acting agents(2) Oral nonabsorbable agents (3)
43、 Topical agents.(4) Combination agents. ClassificationSulfonamides (1)(1)systemic infections.systemic infections. cerebral meningitis cerebral meningitis Tympanitis Tympanitis 中耳炎中耳炎中耳炎中耳炎 Uncomplicated urinary tract infectionsUncomplicated urinary tract infections Combined with TMP in treating comp
44、licated Combined with TMP in treating complicated urinary tract infections,respiratory infections,GI urinary tract infections,respiratory infections,GI infectionsinfections(2) intestinal infections.(2) intestinal infections. Sulfasalazine Sulfasalazine 柳氮磺吡啶柳氮磺吡啶柳氮磺吡啶柳氮磺吡啶(3) infections of burn and
45、wound.(3) infections of burn and wound. Sulfadiazine sliver(Sulfadiazine sliver(磺胺嘧啶银磺胺嘧啶银磺胺嘧啶银磺胺嘧啶银) )Clinical usesSulfonamides (1)Urinary tract disturbances(1)Urinary tract disturbances(2)Hypersensitivity reaction(2)Hypersensitivity reaction(3)Hematopoietic system disturbances(3)Hematopoietic syst
46、em disturbances (4)Kernicterus (4)Kernicterus 脑核黄疸脑核黄疸脑核黄疸脑核黄疸caused by bilirubincaused by bilirubin胆红素胆红素胆红素胆红素 replacement replacement(5)Hepatitis(5)Hepatitis(6)GI disturbances(6)GI disturbances Adverse reactionsSulfonamides (1) Approximately 70%-100% of an oral dose (1) Approximately 70%-100% of
47、an oral dose is absorbed.is absorbed.(2) Sulfonamides are distributed throughout (2) Sulfonamides are distributed throughout all tissues of the body, even in CSF all tissues of the body, even in CSF SulfadiazineSulfadiazine磺胺嘧啶磺胺嘧啶磺胺嘧啶磺胺嘧啶and sulfisoxazoleand sulfisoxazole磺胺异磺胺异磺胺异磺胺异恶唑恶唑恶唑恶唑, may b
48、e effective in meningeal , may be effective in meningeal infections .infections .(3) Sulfonamides readily pass though the (3) Sulfonamides readily pass though the placenta.placenta.ADME of sulfonamidesSulfonamides (4) Sulfonamides are metabolized in the liver by acetylation. (5) Sulfonamides elimina
49、ted mainly in the urine as the unchanged drug and metabolic product. In acid urine, the eliminated are insoluble and may precipitate, thus induced renal disturbance. ADME of sulfonamidesSulfonamides Increase the effects of tolbutamide甲苯磺丁脲甲苯磺丁脲, warfarin , trexan甲氨喋呤甲氨喋呤The reason is: all sulfonamid
50、es are bound in varying degree to plasma protein.Drugs interactionsSulfonamides (1) Oral absorbable agentsShort-acting agentsSulfafurazole(SIZ,菌得清菌得清)Sulfadimidine,(SN2,磺胺二甲嘧啶磺胺二甲嘧啶)Medium-acting agentsSulfadiazine(SD,磺胺嘧啶磺胺嘧啶)Sulfamethoxazole(SMZ,新诺明新诺明)Long-acting agentsSulfamonomethoxine(SMM，磺胺间甲
51、氧嘧啶，磺胺间甲氧嘧啶) Sulfonamides AgentsSulfonamides (2) Oral nonabsorbable agentsSulfasalazine(柳氮磺吡啶柳氮磺吡啶 ) (3) Topical agents.Mafenide(SML, 磺胺米窿磺胺米窿)Sulfadiazine sliver(磺胺嘧啶银磺胺嘧啶银)Sulfacetamide(SA,磺胺醋酰）磺胺醋酰）Sulfonamides AgentsSulfonamides (4) Combination agents. (4) Combination agents. Co-trimoxazole(Co-t
52、rimoxazole(复方新诺明）复方新诺明）复方新诺明）复方新诺明）Trimethoprim(Trimethoprim(甲氧苄啶甲氧苄啶甲氧苄啶甲氧苄啶) in combination ) in combination with Sulfamethoxazole(1:5) exerts a with Sulfamethoxazole(1:5) exerts a synergistic effects. synergistic effects. Pharmcokinetics: The ADME of the two Pharmcokinetics: The ADME of the two a
53、gent is similar.agent is similar.Pharmcodynamics: Co-Pharmcodynamics: Co-block essential block essential enzymes of folate metabolism.enzymes of folate metabolism. Sulfonamides AgentsSulfonamides Typical therapeutic applications of cotrimoxazole (sulfamethoxazole plus trimethoprim).(4) Combination a
54、gents. (4) Combination agents. Co-trimoxazole(Co-trimoxazole(复方新诺明）复方新诺明）复方新诺明）复方新诺明）Clinical Use Clinical Use Chronic and recurrent infections in the Chronic and recurrent infections in the urinary tracturinary tractBacterial respiratory infectionsBacterial respiratory infectionsGI infections (eg.
55、induced by Salmonella)GI infections (eg. induced by Salmonella) Sulfonamides AgentsSulfonamides (4) Combination agents. Co-trimoxazole(复方新诺明）复方新诺明） Adverse reactionThere is no evidence that co-trimoxazole, when given in recommended dose, induced folate deficiency in normal persons.The main untoward
56、effects is hypersensitive reactions( eg. involve the skin). Sulfonamides AgentsSulfonamides Trimethoprim (甲氧苄啶甲氧苄啶)Dihydrofolate reductase inhibitorDrug resistance occurs easily when used alone Nitrofurans (硝基呋喃类硝基呋喃类) Nitrofurantoin(呋喃妥因呋喃妥因）Bactericidal agent Co A inhibitorDNA damageResistance is rareClinical applications: Urinary tract infectionsOther Synthetic antimicrobialOther Synthetic antimicrobialTrimethoprim(甲氧苄啶甲氧苄啶)Nitrofurans(硝基呋喃类硝基呋喃类): Funacillin(呋喃西林呋喃西林) Furantoin(呋喃妥因呋喃妥因) Furazolidone(呋喃唑酮呋喃唑酮, 痢特痢特灵灵)END OF CLASS
