β-lactam antibiotics(β- 内酰胺类抗生素）

Penicillin nucleus. β- lactam is the square at the center.

二十世纪十大分子1900-1910: aspirin

1910-1920: isooctane （异辛烷，与汽车工业有关）1920-1930: penicillin G

1930-1940: polyethene （英国 ICI 科学家偶尔得到， 1933合成， 1939 年应用。大量用于雷达 cable insulation ）1940-1950: nylon 6,6 ( 用于二战，代替丝织物 )

1950-1960: DNA

1960-1970: progestin （黄体激素， contraceptives ）1970-1980: DDT （对鸟、动物有害）1980-1990: fluoxetine, introduced by Eli Lilly in 1986. 到当时为止处方最多的抗抑郁药，在 90 多个国家应用。1990-2000: carbon nanotubes

Penicillins （青霉素类）

Natural penicillins

Penicillin G

Pharmacokinetics:

destroyed easily by gastric acid

distribution widely and 5% across BBB when in meningitis

renal tubular excretion in prototype

Antibacterial spectrum

Antibacterial spectrum: Gram-positive cocci : Staphylococcus infecti

ons Gram-negative cocci: Staphylococcus pneu

moniae infection Gram-positive bacilli: diphtheria （白喉）， t

etanus （破伤风） Leptospira （螺旋体） : leptospirosis （钩端

螺旋体病） Actinomycetes （放线菌）： actinomycosis

（放线菌病）

淋病奈瑟菌

放线菌

放线菌病

Mechanism of penicillin

β-Lactam antibiotics work by binding to transpeptidase and then inhibiting the formation of peptidoglycan cross-links in the bacterial cell wall.

Peptidoglycan （肽聚糖） is a 3D molecule

Cross links are both horizontal and vertical between glycan chains stacked atop one another.

Resistance to penicillins

Structural changes of penicillin binding protein (PBP) naturally

PBP production caused by sensitive or inter-bacterial gene recombination

Decrease of porin

Hydrolysis by β-lactamases

Adverse effects

Allergic reactions

Allergic shock, 0.004% － 0.04%

10% cross-sensitivity between penicillin-derivatives, cephalosporins, and carbapenems

Inquiring history of β-lactam antibiotics use （没有用过青霉素要不要做皮试？）

Skin test before use

Seizure-like reaction when intrathecally administrated in large amount (>20000 U) (seizure model) (inhibition of GABA synthesis, …)

Semi-synthetic penicillins

Penicillin G

Advantages disadvantages

－－－－－－－－－－－－－－－－－－－－－－high efficacy acid-irresistant

low toxicity β-lactamase-irresistant

cheap narrow spectrum

easy to use high allergic reactions

－－－－－－－－－－－－－－－－－－－－－－

6-aminopenicillanic acid (6-APA, 6- 氨基青霉烷酸）

Semi-synthetic penicillins

Penicillin V

resists destruction by gastric juice (oral route OK)

Still β-lactamase-irresistant

Less efficient when penicillin G is effective

Semi-synthetic penicillins

β-lactamase-resistant penicillins

flucloxacillin （氟氯西林 ), oxacillin( 苯唑西林 ), cloxacillin （氯唑西林）

β-lactamase-resistant

Less efficient when penicillin G is effective

Semi-synthetic penicillins

Wide-spectrum penicillins （广谱青霉素）Ampicillin （氨苄西林）， amoxicillin （阿莫西林）

wide spectrum (inhibiting gram positive and negative bacteria)

Acid-resistant

β-lactamase-irresistant

Semi-synthetic penicillins

antipseudomonal penicillins （抗铜绿假单胞菌青霉素） Carbenicillin （羧苄西林）， ticacillin （替卡西林）， piperacillin （哌拉西林）

Antipseudomonal

β-lactamase-irresistant

Less efficient when penicillin G is effective

Semi-synthetic penicillins

Anti-Gram negative bacterial penicillins （抗G- 杆菌青霉素）Mecillinam （美西林） , temocillin （替莫西林）

β-lactamase resistant and effective against Gram negative bacteria

Cephalosporins （头孢菌素类）

Cephalosporins （头孢菌素类）

1948 ， Italian Giuseppe Brotzu

Sardinia, sewer

Cephalosporium acremonium ( 头孢菌）Culture effective against Salmonella typhi （伤寒沙门菌）Cephalosporin C isolated in Oxford, weak activity

7-aminocephalosporanic acid （ 7-ACA, 7- 氨基头孢烯酸）

cephalosporins

General characters:

Wide antibacterial spectrum

High efficacy

Low allergic rate

Partial cross-sensitivity to penicillin (lesser from third generation on)

Certain extent of β-lactamase resistance

cephalosporins

Classification, based mainly on antibacterial properties:

First generation: cefazolin （头孢唑啉）， cephalexin （头孢氨苄）： potent against G+; renal toxicity

Second generation: cefuroxime （头孢呋辛）， cefacolor （头孢克洛）： against G+ & G － ; low renal toxicity

Third generation: ceftriaxone （头孢曲松）， cefoperazone （头孢哌酮）： less against G+, more potent against G － ; very low renal toxicity

Fourth generation: cefepime （头孢吡肟） : potent both against G+ & G － ; no renal toxicity

各代头孢菌素都在临床应用 !!!

Carbapenems （碳青霉烯类）

Other β-lactam penicillins

Imipenem （亚胺培南）

imipenem

Imipenem 亚胺培南

extremely broad spectrum

high efficacy

β-lactamase resistant

hydrolyzed easily by renal dehydropeptidase; co-administered with silastatin（西司他丁） , the enzyme inhibitor

Meropenem （美罗培南）

Dehydropeptidase-resistant

Even wider antibacterial spectrum than imipenem

Cephamycins （头霉素类）

Cephamycins

≈second generation of cephalosporin

Cefoxitin 头孢西丁； Cefmetazole （头孢美唑）

N

SHN

R2O

R1

COOH

O

HOCH3

Oxacephems （氧头孢烯类）

Oxacephems （氧头孢烯类）

Latamoxef （拉氧头孢） wide antibacterial spectrum like third genera

tion of cephalosporins

Strong anti-anaerobic bacterial effect

prolonged bleeding time (even lethal)

No longer available in US

Monocyclic β-lactam antibiotic

单环β-内酰胺抗生素

Monocyclic β-lactam antibiotic

strong activity against susceptible gram-negative bacteria including Pseudomonas aeruginosa.

like aminoglycosides, but no renal toxicity

Aztreonam 氨曲南

β-lactamase inhibitors and compound preparation

β- 内酰胺酶抑制剂及复方制剂

Clavulanic acid 克拉维酸

β-lactamase inhibitor

clavulanic acid （克拉维酸） ; sulbactam（舒巴坦）； tazobactam （他唑巴坦）similarity in chemical structure allows the molecule to act as a competitive inhibitor of β-lactamases to confer β-lactam antibiotics antibacterial activity

co-administered with β-lactam antibiotics:

clavulanic acid + amoxicillin

sulbactam + cefoperazone

Glycopeptide antibiotics 糖肽类and Other antibiotics

Vancomycin （万古霉素）Borneo 婆罗洲丛林土壤

Eli Lilly, EC Kornfeld

vancomycin

Glycopeptide; preventing incorporation of N-acetylmuramic acid (NAM)- and N-acetylglucosamine (NAG)-peptide subunits into the peptidoglycan matrix

Only effective against gram ＋ bacteria including MRSA

Traditionally, drug of “last resort”

VRSA: vancomycin-resistant Staphylococcus aureus

VRE: vancomycin-resistant enterococci

Scanning electron micrographs of vancomycin-resistant Enterococcus

vancomycin

Severe ototoxicity and nephrotoxicity, etc.

being replaced by linezolid （利奈唑胺） and daptomycin （达托霉素）

norvancomycin 去甲万古霉素 ; teicoplanin 替考拉宁≈vancomycin with lower toxicity

Daptomycin 达托霉素

daptomycin

Eli Lilly; Cubist company

Novel cyclic lipopeptide antibiotic 环脂肽抗生素Strong activity against Gram-positive organisms, ev

en multi-resistant bacteria

Fosfomycin 磷霉素

Fosfomycin

Wide spectrum; low toxicity; no cross-resistance and allergy

Inhibiting bacterial cell wall biogenesis (enzyme inhibitor)

Further reading

Fischbach MA, Walsh CT. Antibiotics for emerging pathogens. Science. 2009 Aug 28;325(5944):1089-93.