4 - β-Lactam Antibiotics: Biochemical Modes of Action

Abstract

This chapter focuses on the biochemical modes of action of β-lactam antibiotics. The modes of action of β-lactam antibiotics are quite complex. Penicillin and other β-lactams acylate several specific proteins, the penicillin-binding proteins, to effect the inhibition of the cell-wall assembly. PBPs include penicillin-sensitive enzymes involved in the cross-linking step of peptidoglycan biosynthesis. These enzymes catalyze transpeptidase, D-alanine carboxypeptidase, and endopeptidase reactions in vitro. Several high-molecular-weight PBPs might catalyze penicillin-insensitive transglycosylation of cell-wall disaccharide units too. A combination of genetic and biochemical techniques has been applied to better define the in vivo functions of several PBPs. Penicillin and substrate acylate the same active-site serine residue in each of two D-alanine carboxypeptidases, in accord with the substrate analog hypothesis for the mechanism of penicillin action. X-ray crystallographic studies in progress should help elucidate the detailed mechanisms by which β-lactam antibiotics inhibit sensitive enzymes. Penicillin-induced cell lysis involves several factors, the most important of which is the participation of endogenous autolytic enzymes. The outer membrane of gram-negative bacteria poses a formidable penetration barrier to β-lactam antibiotics, compounding the factors that influence the effectiveness of these compounds as antimicrobial agents.