Chapter 57: Penicillins, Cephalosporins, and Other β-Lactam Antibiotics

INTRODUCTION

The β-lactam antibiotics—penicillins, cephalosporins, carbapenems, and monobactams—share a common structure (β-lactam ring) and mechanism of action (i.e., inhibition of the synthesis of the bacterial peptidoglycan cell wall). Bacterial resistance against the β-lactam antibiotics continues to increase at a dramatic rate. β-Lactamase inhibitors such as clavulanate and avibactam can extend the utility of these antibiotics against β-lactamase–producing organisms. Unfortunately, resistance includes not only production of β-lactamases but also alterations in the bacterial enzymes targeted by β-lactam antibiotics, as well as decreased entry or active efflux of the antibiotic.

ABBREVIATIONS

MECHANISM OF ACTION: INHIBITION OF PEPTIDOGLYCAN SYNTHESIS

Peptidoglycan is a heteropolymeric component of the bacterial cell wall that provides rigid mechanical stability. The β-lactam antibiotics inhibit the last step in peptidoglycan synthesis (Figure 57–1).

In gram-positive microorganisms, the cell wall is 50–100 molecules thick; in gram-negative bacteria, it is only 1 or 2 molecules thick (Figure 57–2A). The peptidoglycan is composed of glycan chains, which are linear strands of two alternating amino sugars (N-acetylglucosamine and N-acetylmuramic acid) that are cross-linked by peptide chains. Peptidoglycan precursor formation takes place in the cytoplasm. The synthesis of UDP–acetylmuramyl-pentapeptide is completed with the addition of a dipeptide, D-alanyl-D-alanine (formed by racemization and condensation of L-alanine). UDP-acetylmuramyl-pentapeptide and UDP-acetylglucosamine are linked (with the release of the uridine nucleotides) to form a long polymer. The cross-link is completed by a transpeptidation reaction that occurs outside the cell membrane (Figure 57–2B).