Lactam antibiotics
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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 )

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β -lactam antibiotics ( β - 内酰胺类抗生素)

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Lactam antibiotics

β-lactam antibiotics(β-内酰胺类抗生素)


Lactam antibiotics

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


Lactam antibiotics

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

Penicillins(青霉素类)


Natural penicillins

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

  • Antibacterial spectrum:

  • Gram-positive cocci : Staphylococcus infections

  • Gram-negative cocci: Staphylococcus pneumoniae infection

  • Gram-positive bacilli: diphtheria(白喉),tetanus(破伤风)

  • Leptospira(螺旋体): leptospirosis(钩端螺旋体病)

  • Actinomycetes(放线菌):actinomycosis(放线菌病)


Lactam antibiotics

淋病奈瑟菌


Lactam antibiotics

放线菌


Lactam antibiotics

放线菌病


Mechanism of penicillin

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 is a 3d molecule

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

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

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

Semi-synthetic penicillins

Penicillin G

Advantages disadvantages

----------------------

high efficacyacid-irresistant

low toxicity β-lactamase-irresistant

cheapnarrow spectrum

easy to use high allergic reactions

----------------------


Lactam antibiotics

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


Semi synthetic penicillins1

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 penicillins2

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 penicillins3

Semi-synthetic penicillins

Wide-spectrum penicillins(广谱青霉素)

  • Ampicillin(氨苄西林),amoxicillin(阿莫西林)

  • wide spectrum (inhibiting grampositive and negative bacteria)

  • Acid-resistant

  • β-lactamase-irresistant


Semi synthetic penicillins4

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 penicillins5

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


Lactam antibiotics

Cephalosporins(头孢菌素类)


Cephalosporins

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


Lactam antibiotics

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


Cephalosporins1

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


Cephalosporins2

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!!!


Lactam antibiotics

Carbapenems(碳青霉烯类)


Other lactam penicillins

Other β-lactam penicillins

  • Imipenem(亚胺培南)


Lactam antibiotics

imipenem


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

Meropenem(美罗培南)

  • Dehydropeptidase-resistant

  • Even wider antibacterial spectrum than imipenem


Lactam antibiotics

Cephamycins(头霉素类)


Cephamycins

Cephamycins

  • ≈second generation of cephalosporin

  • Cefoxitin 头孢西丁;Cefmetazole (头孢美唑)


Lactam antibiotics

Oxacephems(氧头孢烯类)


Oxacephems

Oxacephems(氧头孢烯类)

  • Latamoxef(拉氧头孢)

  • wide antibacterial spectrum like third generation of cephalosporins

  • Strong anti-anaerobic bacterial effect

  • prolonged bleeding time (even lethal)

  • No longer available in US


Lactam antibiotics

Monocyclic β-lactam antibiotic

单环β-内酰胺抗生素


Monocyclic lactam antibiotic

Monocyclic β-lactam antibiotic

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

  • like aminoglycosides, but no renal toxicity

Aztreonam 氨曲南


Lactam antibiotics

β-lactamase inhibitors and compound preparation

β-内酰胺酶抑制剂及复方制剂


Lactam antibiotics

Clavulanic acid 克拉维酸


Lactamase inhibitor

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 conferβ-lactam antibiotics antibacterial activity

  • co-administered with β-lactam antibiotics:

  • clavulanic acid + amoxicillin

  • sulbactam + cefoperazone


Lactam antibiotics

Glycopeptide antibiotics 糖肽类

and Other antibiotics


Vancomycin

Vancomycin(万古霉素)

Borneo婆罗洲丛林土壤

Eli Lilly, EC Kornfeld


Vancomycin1

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


Lactam antibiotics

Scanning electron micrographs of vancomycin-resistant Enterococcus


Vancomycin2

vancomycin

  • Severe ototoxicity and nephrotoxicity, etc.

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


Lactam antibiotics

  • norvancomycin 去甲万古霉素; teicoplanin 替考拉宁

  • ≈vancomycin with lower toxicity


Lactam antibiotics

Daptomycin 达托霉素


Daptomycin

daptomycin

  • Eli Lilly; Cubist company

  • Novel cyclic lipopeptide antibiotic 环脂肽抗生素

  • Strong activity against Gram-positive organisms, even multi-resistant bacteria


Lactam antibiotics

Fosfomycin 磷霉素


Fosfomycin

Fosfomycin

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

  • Inhibiting bacterial cell wall biogenesis(enzyme inhibitor)


Further reading

Further reading

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


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