Beta-lactams
Classes
- Penams eg penicillins
- Clavams: beta-lactamase inhibitors that contain a five-membered ring with
an oxygen heteroatom (eg clavulanic acid)
- Carbapenems eg meropenem, imipenem
- Cephems (cephalosporins)
- Monobactams eg aztreonam
- Oxacephems: oxygen analogues of cephems
Mode of action
Bacteriostatic effect due inhibition of cell wall synthesis by inactivation
of transpeptidases. This is a crucial enzyme in the cross-linking of peptidoglycan -
the basic building block of the cell wall
- act as a false substrate for D-alanyl-D-alanyl transpeptidases
- requires carboxylate or sulfonate group of beta-lactam to react the a
serine residue of transpeptidases (also known as penicillin-binding
proteins) to give an inactive acylated enzyme
- transpeptidases are located in periplasmic space. This is directly
accessible in Gram +ve bacteria but in Gram -ves the drugs need to cross the
outer bacterial cell membrane (passive diffusion) or pass through porin
channels
Bactericidal effect results from indirect mechanisms (mostly activation of
autolytic enzymes)
Only active against rapidly dividing bacteria.
Resistance
- alteration in porin channels limits access to transpeptidases in gram
negative bacteria
- modification of transpeptidases resulting in decreased affinity for beta-lactams
(eg MRSA)
- production of beta-lactamases (most common mechanism). These hydrolyse
beta-lactams at a far higher rate than transpeptidases (1000 beta-lactams
per second cf. 1 per hour). Many beta-lactams have been made resistant to
beta-lactams but beta-lactamases with activity against these new drugs
inevitably develop
- extended spectrum beta-lactamases are a
particular problem. They are capable of hydrolysing penicillins,
broad-spectrum cephalosporins and monobactams. Often associated with
resistance to aminoglycosides and fluoroquinolones
Pharmacodynamics
Further reading
Van Bambeke F. Mechanisms of action. In Armstrong D, Cohen J.
Infectious diseases. Mosby, London, 1999, pp7/1.1-7/1.14 | 
