Synthetic antimicrobial agents (人工合成抗菌药) Huifang Tang tanghuifang@zju.edu.cn

Classification of Synthetic antimicrobial agents Ⅰ. Quinolones(喹诺酮类); Ⅱ. Sulfonamides(磺胺类); Ⅲ. Other synthetic antimicrobial agents: Trimethoprim (甲氧苄啶) Nitrofurans (硝基呋喃类), etc.

Relatively few side effects. Quinolones Quinolones General features Broad 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 Chemistry Derived 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 Chemical structure (萘啶酸) (诺氟沙星) (环丙沙星)

Classification Quinolones Generation Examples 1 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

Summary of antimicrobial spectrum of quinolones.

Typical therapeutic applications of uoroquinolones.

Quinolones 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 distribution Clinical applications Uncomplicated urinary tract infections

Quinolones 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 bacilli Ciprofloxacin remains the quinolone most active against Pseudomonas aeruginosa

Quinolones Second-generation quinolones (1969-1979) Quinolones Active against gram-positive and gram-negative bacteria, mycobacteria, mycoplasma支原体and legionella species军团杆菌属.  Longer half-lives due to slow elimination, distribution into many tissues and body fluids and penetration into human cells. 

Quinolones 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 Fourth-generation agents (1997- ) Quinolones 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 Antimicrobial activity & spectrum Quinolones (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 Antimicrobial activity & spectrum Quinolones (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 Mechanism of actions Quinolones 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 involved in the separation process of the DNA daughter chains after chromosome duplication.

Quinolones Mechanism of actions Quinolones The quinolone antibiotics target bacterial DNA gyrase (gram-negative bacteria) Topoisomerase IV (gram- positive bacteria).

Mechanism of action Quinolones 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 Inhibition of DNA gyrase →prevents the relaxation of positively supercoiled DNA that is required for normal transcription and replication. Inhibition of topoisomerase IV → interferes with separation of replicated chromosomal DNA into the respective daughter cells during cell division.

Resistance Mechanism Quinolones Intrinsic resistance is rare With a frequency of about one in 107–109, especially among staphylococci, pseudomonas, and serratia(沙雷氏菌).

Quinolones Resistance Mechanism (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 efflex by a active transport protein pump. (4) Plasmid mediated resistance.

ADME of Quinolones (1) Well absorbed after oral administration. (2) Distributed widely in body tissue, even in CSF. (3) Excreted mainly in urine. Routes of elimination differ among the Quinolones.

Clinical Uses Urinary tract infections. Quinolones Clinical Uses Urinary tract infections. The main indication for quinolones In the treatment of uncomplicated and complicated UTIs, cure rates can exceed 90% and 80%, respectively. Potent agents to use against Haemophilus ducreyi (软性下疳嗜血杆菌) and penicillin-sensitive and penicillin-resistant Neisseria gonorrhoeae淋(病双)球菌.

Clinical Uses Quinolones (2) GI and abdominal infections. Excellent in vitro activity against many enteric pathogens, including Escherichia coli大肠杆菌, Aeromonas气单胞菌属, Shigella志贺(氏)杆菌, Salmonella沙门氏菌, Campylobacter弯曲杆菌属, Vibrio弧菌属, and Yersinia species耶尔森菌 Furthermore, quinolone drug concentrations in feces are exceedingly high.

Clinical Uses (3) Respiratory tract infections. Quinolones Clinical Uses (3) Respiratory tract infections. Have inferior activity against streptococci链球菌and should not be used as primary therapy for common upper respiratory tract infections. Alternatives for treatment of acute exacerbation of chronic bronchitis in patients with obstructive pulmonary disease who are intolerant of or have developed resistance to first-line antibiotics. antibiotics with activity against Streptococcus pneumoniae, Haemophilus influenzae流感(嗜血)杆菌, and Moraxella catarrhalis粘膜炎莫拉菌. (4) Other infections： Bone, joint and soft tissue infections.

Adverse reactions Quinolones (1)Gastrointestinal effects. The most common reactions (2)CNS side effects. Penetrate BBB→ GABA↓ (3)Allergic reaction. Skin rashses, itchs, angioneuroedema , etc. Photosensitivity (4)other effects. Cardiac toxicity： Q-T interval↑ Liver and renal injury

Adverse reactions (4)other effects. Muscle skeletal system Quinolones Adverse reactions (4)other effects. Muscle skeletal system Amyasthenia 肌无力, myosalgia肌痛, joint pain and inflammation Increase intracranial pressure in infants

Quinolones agents Pipemidic acid (吡哌酸) Norfloxacin (诺氟沙星) Ciprofloxacin (环丙杀星) Ofloxacin（氧氟沙星） Levofloxacin（左氧氟沙星） Lomefloxacin（洛美沙星） Fleroxacin（氟罗沙星） Sparfloxacin（司帕沙星）

Quinolones Pharmacokinetic Properties of Fluoroquinolones

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 注意研究结构变幅更大的喹诺酮 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(pazufloxacin )、鲁利沙星(prulifloxacin ) 非氟喹诺酮格林沙星(garenoxacin )

Sulfonamides

Sulfonamides Sulfonamides

Antimicrobial activity Sulfonamides Antimicrobial activity (1) Sulfonamides have a wide range of antimicrobial activity. G+,G- bacteria, Nocardia 诺卡菌属, Bedsonia trachomatis沙眼衣原体, etc. Enteric bacteria etc. less effective Rickett's organism (2) Sulfonamides exert only bacteriostatic effect.

Sulfonamides Mechanism of action Structural analogs and competitive antagonists of para-aminobenzoic acid (对氨基苯甲酸 PABA) Prevent normal bacterial utilization of PABA for the synthesis of folic acid.

Sulfonamides Mechanism of action

Mechanism of Resistance Sulfonamides Mechanism of Resistance Originate by random mutation and selection or by transfer of resistance by plasmaides. Such resistance usually is persistent and irreversible.

Mechanism of Resistance Sulfonamides Mechanism of Resistance The resistance characterized by: (1)A lower affinity for sulfonamides by the dihydropteroate synthase (2)Decreased cell permeability or active efflux of the drug (3)An alternative pathway to synthesis the essential metabolites (4)An increased production of essential metaboltes

Classification Sulfonamides (1) Oral absorbable agents Short-acting agents Medium-acting agents Long-acting agents (2) Oral nonabsorbable agents (3) Topical agents. (4) Combination agents.

Clinical uses Sulfonamides systemic infections. cerebral meningitis Tympanitis 中耳炎 Uncomplicated urinary tract infections Combined with TMP in treating complicated urinary tract infections,respiratory infections,GI infections (2) intestinal infections. Sulfasalazine 柳氮磺吡啶 (3) infections of burn and wound. Sulfadiazine sliver(磺胺嘧啶银)

Adverse reactions Sulfonamides (1)Urinary tract disturbances (2)Hypersensitivity reaction (3)Hematopoietic system disturbances↓ (4)Kernicterus 脑核黄疸 caused by bilirubin胆红素 replacement (5)Hepatitis (6)GI disturbances

ADME of sulfonamides Sulfonamides (1) Approximately 70%-100% of an oral dose is absorbed. (2) Sulfonamides are distributed throughout all tissues of the body, even in CSF Sulfadiazine磺胺嘧啶and sulfisoxazole磺胺异恶唑, may be effective in meningeal infections . (3) Sulfonamides readily pass though the placenta.

Sulfonamides ADME of sulfonamides (4) Sulfonamides are metabolized in the liver by acetylation. (5) Sulfonamides eliminated 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.

Sulfonamides Drugs interactions Increase the effects of tolbutamide甲苯磺丁脲, warfarin , trexan甲氨喋呤 The reason is: all sulfonamides are bound in varying degree to plasma protein.

Sulfonamides Agents Sulfonamides (1) Oral absorbable agents Short-acting agents Sulfafurazole(SIZ,菌得清) Sulfadimidine,(SN2,磺胺二甲嘧啶) Medium-acting agents Sulfadiazine(SD,磺胺嘧啶) Sulfamethoxazole(SMZ,新诺明) Long-acting agents Sulfamonomethoxine(SMM，磺胺间甲氧嘧啶)

Sulfonamides Agents (2) Oral nonabsorbable agents Sulfasalazine(柳氮磺吡啶 ) (3) Topical agents. Mafenide(SML, 磺胺米窿) Sulfadiazine sliver(磺胺嘧啶银) Sulfacetamide(SA,磺胺醋酰）

Sulfonamides Agents Sulfonamides (4) Combination agents. Co-trimoxazole(复方新诺明） Trimethoprim(甲氧苄啶) in combination with Sulfamethoxazole(1:5) exerts a synergistic effects. Pharmcokinetics: The ADME of the two agent is similar. Pharmcodynamics: Co-block essential enzymes of folate metabolism.

Typical therapeutic applications of cotrimoxazole (sulfamethoxazole plus trimethoprim).

Sulfonamides Agents Sulfonamides (4) Combination agents. Co-trimoxazole(复方新诺明） Clinical Use Chronic and recurrent infections in the urinary tract Bacterial respiratory infections GI infections (eg. induced by Salmonella)

Sulfonamides Agents (4) Combination agents. Co-trimoxazole(复方新诺明） Adverse reaction There is no evidence that co-trimoxazole, when given in recommended dose, induced folate deficiency in normal persons. The main untoward effects is hypersensitive reactions( eg. involve the skin).

Other Synthetic antimicrobial Trimethoprim (甲氧苄啶) Dihydrofolate reductase inhibitor Drug resistance occurs easily when used alone Nitrofurans (硝基呋喃类) Nitrofurantoin(呋喃妥因） Bactericidal agent Co A inhibitor→DNA damage Resistance is rare Clinical applications: Urinary tract infections

Other Synthetic antimicrobial Trimethoprim(甲氧苄啶) Nitrofurans(硝基呋喃类): Funacillin(呋喃西林) Furantoin(呋喃妥因) Furazolidone(呋喃唑酮, 痢特灵)

END OF CLASS