synthetic antimicrobial agents ( 人工合成抗菌药 )

Synthetic antimicrobial Synthetic antimicrobial agentsagents(( 人工合成抗菌药人工合成抗菌药 ))

Huifang Tang [email protected]

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.

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.

QuinolonesQuinolonesQuinolones

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 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

ClassificationQuinolones

Summary of antimicrobial spectrum of quinolones.

Typical therapeutic applications of uoroquinolones.

First-generation agents(1962-1969) First-generation agents(1962-1969)

Nalidixic acid, Nalidixic acid, 萘啶酸萘啶酸•The first generation drug of the quinolone The first generation drug of the quinolone antibioticsantibiotics •Moderate gram-negative activity and minimal Moderate gram-negative activity and minimal systemic distributionsystemic distributionClinical applications Clinical applications • Uncomplicated urinary tract infectionsUncomplicated urinary tract infections


Second-generation quinolones Second-generation quinolones (1969-1979)(1969-1979)

Pipemidic acid Pipemidic acid 吡哌酸吡哌酸 CinoxacinCinoxacin 西诺沙星西诺沙星

•Expanded gram-negative activity and atypical Expanded gram-negative activity and atypical pathogen coverage, but limited gram-positive pathogen coverage, but limited gram-positive activity. activity. •Most active against aerobic gram-negative Most active against aerobic gram-negative bacillibacilli•Ciprofloxacin remains the quinolone most Ciprofloxacin remains the quinolone most active against Pseudomonas aeruginosaactive against Pseudomonas aeruginosa


Second-generation quinolones Second-generation quinolones (1969-1979)(1969-1979)

•Active against gram-positive and gram-Active against gram-positive and gram-negative bacteria, mycobacteria, negative bacteria, mycobacteria, mycoplasmamycoplasma 支原体支原体 and legionella speciesand legionella species军团杆菌属军团杆菌属 . . •Longer half-lives due to slow Longer half-lives due to slow elimination, distribution into many elimination, distribution into many tissues and body fluids and penetration tissues and body fluids and penetration into human cells. into human cells.


Third-generation quinolones Third-generation quinolones (1980-1996)(1980-1996) Norfloxacin Norfloxacin 诺氟沙星诺氟沙星，， Levofloxacin Levofloxacin 左氧氟沙星左氧氟沙星，， Ciprofloxacin Ciprofloxacin 环丙沙星环丙沙星，， Ofloxacin Ofloxacin 氧氟沙星氧氟沙星，， Sparfloxacin Sparfloxacin 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 Retain expanded gram-negative and atypical intracellular activity but have atypical intracellular activity but have improved gram-positive coverageimproved gram-positive coverage


Fourth-generation agents Fourth-generation agents (1997- )(1997- ) Grepafloxacin Grepafloxacin 格帕沙星，格帕沙星， Clinafloxacin Clinafloxacin 克林克林沙星，沙星， Gatifloxacin Gatifloxacin 加替沙星，加替沙星， Moxifloxacin Moxifloxacin 莫西沙星莫西沙星•Improve gram-positive coverage, Improve gram-positive coverage, maintain gram-negative coverage, and maintain gram-negative coverage, and gain anaerobic coverage.gain anaerobic coverage.


Antimicrobial activity & Antimicrobial activity & spectrumspectrum

(1) Bactericidal and have significant PAE. (1) Bactericidal and have significant PAE.

(2)Excellent activity against aerobic (2)Excellent activity against aerobic gram-negative bacteria, some agents gram-negative bacteria, some agents have activity against Pesudomonas. have activity against Pesudomonas.

(3) Several newer agents with improved (3) Several newer agents with improved activity against aerobic gram-positive activity against aerobic gram-positive bacteria.bacteria.


Antimicrobial activity & Antimicrobial activity & spectrumspectrum

(4) They also are effective against (4) They also are effective against Chlamydia spp.Chlamydia spp. （衣原体）（衣原体） , Legionella , Legionella pneumophila(pneumophila( 军团菌军团菌 ) ,anaerobic ) ,anaerobic bacteria, mycobacteria(bacteria, mycobacteria( 分枝杆菌分枝杆菌 ).).

(5) Some agents have limited activity (5) Some agents have limited activity against multiple-resistance strains.against multiple-resistance strains.

（（ 66 ）） Bactericidal concentration≥ Bactericidal concentration≥ bacteriostatic concentrationbacteriostatic concentration


Mechanism of actionsMechanism of actions Topoisomerases :Topoisomerases : enzymes that control enzymes that control

and modify the topological states of and modify the topological states of DNA in cells.DNA in cells.

• Topoisomerase ITopoisomerase I ，， IIIIII catalyse merely catalyse merely the relaxation of DNAthe relaxation of DNA

• Topoisomerase II Topoisomerase II （（ DNA gyraseDNA gyrase ）） catalyse the supercoiling of DNAcatalyse the supercoiling of DNA

• Topoisomerase IVTopoisomerase IV involved in the involved in the separation process of the DNA separation process of the DNA daughter chains after chromosome daughter chains after chromosome duplication.duplication.


Mechanism of actions Mechanism of actions

The quinolone antibiotics target The quinolone antibiotics target bacterial bacterial

• DNA gyrase (gram-negative DNA gyrase (gram-negative bacteria) bacteria)

• Topoisomerase IV (gram- positive Topoisomerase IV (gram- positive bacteria).bacteria).


•Topoisomerase IV : involved in the separation Topoisomerase IV : involved in the separation process of the DNA daughter chains after process of the DNA daughter chains after chromosome duplication.chromosome duplication.•unable to catalyse the supercoiling of DNA, unable to catalyse the supercoiling of DNA, merely its relaxation. merely its relaxation. •The enzyme comprises two subunits, ParC The enzyme comprises two subunits, ParC and ParE.and ParE.•The ParC protein is homologous to the gyrase The ParC protein is homologous to the gyrase A protein, while the ParE subunit is A protein, while the ParE subunit is homologous to the gyrase B protein.homologous to the gyrase B protein.

MechanismMechanism ofof actionaction

Quinolones

•Inhibition of topoisomerase IV → Inhibition of topoisomerase IV → interferes interferes with separation of replicated chromosomal with separation of replicated chromosomal DNA into the respective daughter cells DNA into the respective daughter cells during cell division.during cell division.

•Inhibition of DNA gyrase →Inhibition of DNA gyrase →prevents the prevents the relaxation of positively supercoiled DNA that is relaxation of positively supercoiled DNA that is required for normal transcription and required for normal transcription and replicationreplication..

MechanismMechanism ofof actionactionQuinolones

•Intrinsic resistance is rareIntrinsic resistance is rare

•With a frequency of about one in With a frequency of about one in 101077–10–1099, especially among , especially among staphylococci, pseudomonas, and staphylococci, pseudomonas, and serratia(serratia( 沙雷氏菌沙雷氏菌 ).).

ResistanceResistance MechanismMechanism

Quinolones

(1) Mutation of (1) Mutation of the gyrA genethe gyrA gene that that encoded the A subunit polypeptide encoded the A subunit polypeptide can confer resistance to these drugs.can confer resistance to these drugs.

(2) Mutation of (2) Mutation of the gene cfxB and nfxBthe gene cfxB and nfxB that encoded the porin decreased that encoded the porin decreased permeability of cell membrance. permeability of cell membrance.

(3) The high expression of (3) The high expression of norA genenorA gene (encoded active pump protein) (encoded active pump protein) increased drugs efflex by a active increased drugs efflex by a active transport protein pump.transport protein pump.

(4) Plasmid mediated resistance.(4) Plasmid mediated resistance.

ResistanceResistance MechanismMechanismQuinolones

(1) Well absorbed after oral (1) Well absorbed after oral administration.administration.

(2) Distributed widely in body (2) Distributed widely in body tissue, even in CSF.tissue, even in CSF.

(3) Excreted mainly in urine. (3) Excreted mainly in urine. • Routes of elimination differ Routes of elimination differ

among the Quinolones.among the Quinolones.

ADMEADME ofof QuinolonesQuinolones

Quinolones

(1)(1)Urinary tract infections.Urinary tract infections.• The main indication for quinolones The main indication for quinolones • In the treatment of uncomplicated In the treatment of uncomplicated

and complicated UTIs, cure rates and complicated UTIs, cure rates can exceed 90% and 80%, can exceed 90% and 80%, respectively.respectively.

• Potent agents to use against Potent agents to use against Haemophilus ducreyi (Haemophilus ducreyi ( 软性下疳嗜血杆软性下疳嗜血杆菌菌 ) and penicillin-sensitive and ) and penicillin-sensitive and penicillin-resistant Neisseria penicillin-resistant Neisseria gonorrhoeaegonorrhoeae 淋淋 (( 病双病双 )) 球菌球菌 ..

ClinicalClinical UsesUsesQuinolones

(2) GI and abdominal infections.(2) GI and abdominal infections.• Excellent in vitro activity against Excellent in vitro activity against

many enteric pathogens, including many enteric pathogens, including Escherichia coliEscherichia coli 大肠杆菌大肠杆菌 , Aeromonas, Aeromonas 气气单胞菌属单胞菌属 , Shigella, Shigella 志贺 ( 氏 ) 杆菌 , , SalmonellaSalmonella 沙门氏菌 , Campylobacter, Campylobacter 弯曲杆菌属 , Vibrio, Vibrio 弧菌属 , and Yersinia , and Yersinia speciesspecies 耶尔森菌耶尔森菌

• Furthermore, quinolone drug Furthermore, quinolone drug concentrations in feces are concentrations in feces are exceedingly high.exceedingly high.


(3) Respiratory tract infections.(3) Respiratory tract infections.• Have inferior activity against streptococciHave inferior activity against streptococci 链球菌链球菌

and should not be used as primary therapy for and should not be used as primary therapy for common upper respiratory tract infections. common upper respiratory tract infections.

• Alternatives 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 resistance 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 (( 嗜血嗜血 ))杆菌杆菌 , and Moraxella catarrhalis, and Moraxella catarrhalis 粘膜炎莫拉菌粘膜炎莫拉菌 . .

(4) Other infections(4) Other infections ：： Bone, joint Bone, joint and soft tissue infections.and soft tissue infections.


(1)Gastrointestinal effects.(1)Gastrointestinal effects.• The most common reactions The most common reactions

(2)CNS side effects.(2)CNS side effects.• Penetrate BBB→ GABA↓Penetrate BBB→ GABA↓

(3)Allergic reaction.(3)Allergic reaction.• Skin rashses, itchs, angioneuroedema , Skin rashses, itchs, angioneuroedema ,

etc.etc.• PhotosensitivityPhotosensitivity

(4)other effects.(4)other effects.• Cardiac toxicityCardiac toxicity ：： Q-T interval↑Q-T interval↑• Liver and renal injuryLiver and renal injury

AdverseAdverse reactionsreactions

Quinolones

(4)other effects.(4)other effects.• Muscle skeletal system Muscle skeletal system • Amyasthenia Amyasthenia 肌无力肌无力 , ,

myosalgiamyosalgia 肌痛肌痛 , joint pain and , joint pain and inflammationinflammation

• Increase intracranial Increase intracranial pressure in infantspressure in infants

AdverseAdverse reactionsreactions

Quinolones

• Pipemidic acid (Pipemidic acid ( 吡哌酸吡哌酸 ))• Norfloxacin (Norfloxacin ( 诺氟沙星诺氟沙星 ))• Ciprofloxacin (Ciprofloxacin ( 环丙杀星环丙杀星 ))• OfloxacinOfloxacin （氧氟沙星）（氧氟沙星）• LevofloxacinLevofloxacin （左氧氟沙星）（左氧氟沙星）• LomefloxacinLomefloxacin （洛美沙星）（洛美沙星）• FleroxacinFleroxacin （氟罗沙星）（氟罗沙星）• SparfloxacinSparfloxacin （司帕沙星）（司帕沙星）

QuinolonesQuinolones agentsagents

Quinolones

PharmacokineticPharmacokinetic PropertiesProperties ofof FluoroquinolonesFluoroquinolones

Quinolones

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

– 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 )

SulfonamidesSulfonamides

SulfonamideSulfonamidess

Sulfonamides

(1) (1) SulfonamidesSulfonamides have a wide range of have a wide range of antimicrobial activity.antimicrobial activity.

• G+,G- bacteria, Nocardia G+,G- bacteria, Nocardia 诺卡菌属诺卡菌属 , , Bedsonia trachomatisBedsonia trachomatis 沙眼衣原体沙眼衣原体 , etc., etc.

• Enteric bacteria etc. less effectiveEnteric bacteria etc. less effective• Rickett's organismRickett's organism

(2) (2) SulfonamidesSulfonamides exert only bacteriostatic exert only bacteriostatic effect.effect.

AntimicrobialAntimicrobial activityactivity

Sulfonamides

• Structural analogs and Structural analogs and competitive antagonists competitive antagonists of para-aminobenzoic acid of para-aminobenzoic acid (( 对氨基苯甲酸对氨基苯甲酸 PABA) PABA)

• Prevent normal bacterial Prevent normal bacterial utilization of PABA for the utilization of PABA for the synthesis of folic acid. synthesis of folic acid.

Mechanism of actionMechanism of action

Sulfonamides

Mechanism of actionMechanism of action

Sulfonamides

• Originate by random Originate by random mutation and selection or mutation and selection or by transfer of resistance by transfer of resistance by plasmaides. by plasmaides.

• Such resistance usually is Such resistance usually is persistent and persistent and irreversible. irreversible.

Mechanism of ResistanceMechanism of Resistance

Sulfonamides

The resistance characterized by:The resistance characterized by:(1)A lower affinity for sulfonamides (1)A lower affinity for sulfonamides

by the dihydropteroate synthaseby the dihydropteroate synthase(2)Decreased cell permeability or (2)Decreased cell permeability or

active efflux of the drugactive efflux of the drug(3)An alternative pathway to (3)An alternative pathway to

synthesis the essential metabolitessynthesis the essential metabolites(4)An increased production of (4)An increased production of

essential metaboltesessential metaboltes

Mechanism of ResistanceMechanism of Resistance

Sulfonamides

(1) Oral absorbable agents(1) Oral absorbable agents• Short-acting agentsShort-acting agents• Medium-acting agentsMedium-acting agents• Long-acting agentsLong-acting agents

(2) Oral nonabsorbable (2) Oral nonabsorbable agents agents

(3) Topical agents.(3) Topical agents.

(4) Combination agents. (4) Combination agents.

ClassificationClassification

Sulfonamides

(1)(1)systemic infections.systemic infections.• cerebral meningitis cerebral meningitis • Tympanitis Tympanitis 中耳炎中耳炎• Uncomplicated urinary tract infectionsUncomplicated urinary tract infections• Combined with TMP in treating complicated Combined with TMP in treating complicated

urinary tract infections,respiratory urinary tract infections,respiratory infections,GI infectionsinfections,GI infections

(2) intestinal infections.(2) intestinal infections.• Sulfasalazine Sulfasalazine 柳氮磺吡啶柳氮磺吡啶(3) infections of burn and wound.(3) infections of burn and wound.• Sulfadiazine sliver(Sulfadiazine sliver( 磺胺嘧啶银磺胺嘧啶银 ))

ClinicalClinical usesuses

Sulfonamides

(1)Urinary tract disturbances(1)Urinary tract disturbances

(2)Hypersensitivity reaction(2)Hypersensitivity reaction

(3)Hematopoietic system disturbances↓(3)Hematopoietic system disturbances↓

(4)Kernicterus (4)Kernicterus 脑核黄疸脑核黄疸• caused by bilirubincaused by bilirubin 胆红素胆红素 replacementreplacement

(5)Hepatitis(5)Hepatitis

(6)GI disturbances(6)GI disturbances

Adverse reactionsAdverse reactions

Sulfonamides

(1) Approximately 70%-100% of an oral (1) Approximately 70%-100% of an oral dose is absorbed.dose is absorbed.

(2) Sulfonamides are distributed (2) Sulfonamides are distributed throughout all tissues of the body, throughout all tissues of the body, even in CSF even in CSF

• SulfadiazineSulfadiazine 磺胺嘧啶磺胺嘧啶 and sulfisoxazoleand sulfisoxazole磺胺异恶唑磺胺异恶唑 , may be effective in , may be effective in meningeal infections .meningeal infections .

(3) Sulfonamides readily pass though (3) Sulfonamides readily pass though the placenta.the placenta.

ADME of sulfonamidesADME of sulfonamides

Sulfonamides

(4) Sulfonamides are metabolized (4) Sulfonamides are metabolized in the liver by acetylation. in the liver by acetylation.

(5) Sulfonamides eliminated mainly (5) Sulfonamides eliminated mainly in the urine as the unchanged in the urine as the unchanged drug and metabolic product. drug and metabolic product.

• In acid urine, the eliminated are In acid urine, the eliminated are insoluble and may precipitate, insoluble and may precipitate, thus induced renal disturbance.thus induced renal disturbance.

ADME of sulfonamidesADME of sulfonamides

Sulfonamides

• Increase the effects of Increase the effects of tolbutamidetolbutamide 甲苯磺丁脲甲苯磺丁脲 , , warfarin , trexanwarfarin , trexan 甲氨喋呤甲氨喋呤

• The reason is: The reason is: all sulfonamides all sulfonamides are bound in varying degree to are bound in varying degree to plasma protein.plasma protein.

Drugs interactionsDrugs interactions

Sulfonamides

(1) Oral absorbable agents(1) Oral absorbable agents• Short-acting agentsShort-acting agents

Sulfafurazole(SIZ,Sulfafurazole(SIZ, 菌得清菌得清 ))

Sulfadimidine,(SN2,Sulfadimidine,(SN2, 磺胺二甲嘧啶磺胺二甲嘧啶 ))• Medium-acting agentsMedium-acting agents

Sulfadiazine(SD,Sulfadiazine(SD, 磺胺嘧啶磺胺嘧啶 ))

Sulfamethoxazole(SMZ,Sulfamethoxazole(SMZ, 新诺明新诺明 ))• Long-acting agentsLong-acting agents

Sulfamonomethoxine(SMMSulfamonomethoxine(SMM ，磺胺间甲氧，磺胺间甲氧嘧啶嘧啶 ))

SulfonamidesSulfonamides AgentsAgents

Sulfonamides

(2) Oral nonabsorbable agents(2) Oral nonabsorbable agents

Sulfasalazine(Sulfasalazine( 柳氮磺吡啶柳氮磺吡啶 ) )

(3) Topical agents.(3) Topical agents.

Mafenide(SML, Mafenide(SML, 磺胺米窿磺胺米窿 ))

Sulfadiazine sliver(Sulfadiazine sliver( 磺胺嘧啶银磺胺嘧啶银 ))

Sulfacetamide(SA,Sulfacetamide(SA, 磺胺醋酰）磺胺醋酰）


Sulfonamides

(4) Combination agents. (4) Combination agents. • Co-trimoxazole(Co-trimoxazole( 复方新诺明）复方新诺明）• Trimethoprim(Trimethoprim( 甲氧苄啶甲氧苄啶 ) in ) in

combination with combination with Sulfamethoxazole(1:5) exerts a Sulfamethoxazole(1:5) exerts a synergistic effects. synergistic effects.

• Pharmcokinetics: The ADME of the Pharmcokinetics: The ADME of the two agent is similar.two agent is similar.

• Pharmcodynamics: Co-Pharmcodynamics: Co-block block essential enzymes of folate essential enzymes of folate metabolism.metabolism.


Sulfonamides

Typical therapeutic applications of cotrimoxazole (sulfamethoxazole plus trimethoprim).

(4) Combination agents. (4) Combination agents. • Co-trimoxazole(Co-trimoxazole( 复方新诺明）复方新诺明）Clinical Use Clinical Use • Chronic and recurrent infections in Chronic and recurrent infections in

the urinary tractthe urinary tract• Bacterial respiratory infectionsBacterial respiratory infections• GI infections (eg. induced by GI infections (eg. induced by

Salmonella)Salmonella)


Sulfonamides

(4) Combination agents. (4) Combination agents. • Co-trimoxazole(Co-trimoxazole( 复方新诺明）复方新诺明） Adverse reactionAdverse reaction• There is no evidence that co-trimoxazole, There is no evidence that co-trimoxazole,

when given in recommended dose, induced when given in recommended dose, induced folate deficiency in normal persons.folate deficiency in normal persons.

• The main untoward effects is hypersensitive The main untoward effects is hypersensitive reactions( eg. involve the skin).reactions( eg. involve the skin).


Sulfonamides

Trimethoprim (Trimethoprim ( 甲氧苄啶甲氧苄啶 ))• Dihydrofolate reductase inhibitorDihydrofolate reductase inhibitor• Drug resistance occurs easily when used Drug resistance occurs easily when used

alonealone Nitrofurans (Nitrofurans ( 硝基呋喃类硝基呋喃类 ))

Nitrofurantoin(Nitrofurantoin( 呋喃妥因呋喃妥因））• Bactericidal agent Bactericidal agent • Co A inhibitor→DNA damageCo A inhibitor→DNA damage• Resistance is rareResistance is rare

• Clinical applications:Clinical applications: Urinary tract infectionsUrinary tract infections

OtherOther SyntheticSynthetic antimicrobialantimicrobial

Other Synthetic Other Synthetic antimicrobialantimicrobial

•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 CLASSEND OF CLASS

synthetic antimicrobial agents ( 人工合成抗菌药 )

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