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Patrick An Introduction to Medicinal Chemistry 3/e Chapter 16 ANTIBACTERIAL AGENTS

Patrick An Introduction to Medicinal Chemistry 3/e Chapter 16 ANTIBACTERIAL AGENTS Part 3: Other lactams. Newer b-Lactam Antibiotics. Thienamycin (Merck 1976)(from Streptomyces cattleya). Potent and wide range of activity vs Gram +ve and Gram -ve bacteria

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Patrick An Introduction to Medicinal Chemistry 3/e Chapter 16 ANTIBACTERIAL AGENTS

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  1. Patrick An Introduction to Medicinal Chemistry 3/e Chapter 16 ANTIBACTERIAL AGENTS Part 3: Other lactams

  2. Newer b-Lactam Antibiotics Thienamycin (Merck 1976)(from Streptomyces cattleya) • Potent and wide range of activity vs Gram +ve and Gram -ve bacteria • Active vs. Pseudomonas aeruginosa • Low toxicity • High resistance to b-lactamases • Poor stability in solution (ten times less stable than Pen G)

  3. Imipenem Meropenem Ertapenem(2002) Newer b-Lactam Antibiotics Thienamycinanalogues used in the clinic

  4. Nocardicin A Newer b-Lactam Antibiotics Nocardicins (Fujisawa 1975) • Monocyclic b-lactam ring - monobactams • Moderately active in vitro vs narrow group of Gram -ve bacteria • Active vs. Pseusomonas aeruginosa • Inactive vs. Gram +ve bacteria • Different spectrum of activity from penicillins • Thought to operate by a different mechanism from penicillins • Low toxicity

  5. Aztreonam Newer b-Lactam Antibiotics Clinically useful monobactam • Administered by intravenous injection • Can be used for patients with allergies to penicillins • and cephalosporins • No activity vs. Gram +ve or anaerobic bacteria • Active vs. Gram -ve aerobic bacteria

  6. b-Lactamase Inhibitors Clavulanic acid (Beechams 1976)(from Streptomyces clavuligerus) • Weak, unimportant antibacterial activity • Powerful irreversible inhibitor of b-lactamases - suicide substrate • Used as a sentry drug for ampicillin • Augmentin = ampicillin + clavulanic acid • Allows less ampicillin per dose and an increased activity spectrum • Timentin = ticarcillin + clavulanic acid

  7. 1 2 N N H H 2 2 O H 3 4 5 b-Lactamase Inhibitors Clavulanic acid - mechanism of action

  8. Sulbactam Tazobactam b-Lactamase Inhibitors Penicillanic acid sulfone derivatives • Suicide substrates for b-lactamase enzymes • Sulbactam has a broader spectrum of activity vs b-lactamases than clavulanic acid, but is less potent • Unasyn = ampicillin + sulbactam • Tazobactam has a broader spectrum of activity vs b-lactamases than clavulanic acid, and has similar potency • Tazocin or Zosyn = piperacillin + tazobactam

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