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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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slide3
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
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)
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 efficacy acid-irresistant

low toxicity β-lactamase-irresistant

cheap narrow spectrum

easy to use high allergic reactions

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

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

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
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!!!
other lactam penicillins
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
Meropenem(美罗培南)
  • Dehydropeptidase-resistant
  • Even wider antibacterial spectrum than imipenem
cephamycins
Cephamycins
  • ≈second generation of cephalosporin
  • Cefoxitin 头孢西丁;Cefmetazole (头孢美唑)
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
slide36
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

slide38
β-lactamase inhibitors and compound preparation

β-内酰胺酶抑制剂及复方制剂

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
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
vancomycin2
vancomycin
  • Severe ototoxicity and nephrotoxicity, etc.
  • being replaced by linezolid(利奈唑胺)and 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
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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