1. An Introduction to Medicinal Chemistry 3/e
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. Newer b-Lactam Antibiotics
Thienamycin analogues used in the clinic
Imipenem
Ertapenem(2002)
Meropenem

4. Newer b-Lactam Antibiotics
Nocardicins (Fujisawa 1975)
Nocardicin A
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. Newer b-Lactam Antibiotics
Clinically useful monobactam
Aztreonam
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. b-Lactamase Inhibitors
Clavulanic acid - mechanism of action O H N 2 1 2 N H 3 4 5

8. b-Lactamase Inhibitors
Penicillanic acid sulfone derivatives
Sulbactam
Tazobactam
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