The β-lactam antibiotics—penicillins, cephalosporins, and carbapenems—share a common structure and mechanism of action, 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 can extend the utility of these drugs against β-lactamase-producing organisms. Unfortunately, resistance includes not only production of β-lactamases but also alterations in or acquisition of novel penicillin-binding proteins (PBPs) and decreased entry and/or active efflux of the antibiotic. To a dangerous degree, we are re-entering the pre-antibiotic era, with many nosocomial gram-negative bacterial infections resistant to all available antibiotics.
MECHANISM OF ACTION: INHIBITION OF PEPTIDOGLYCAN SYNTHESIS. Peptidoglycan is a heteropolymeric component of the cell wall that provides rigid mechanical stability. The β-lactam antibiotics inhibit the last step in peptidoglycan synthesis (Figure 53-1).
Action of β-lactam antibiotics in Staphylococcus aureus. The bacterial cell wall consists of glycopeptide polymers (a NAM-NAG amino-hexose backbone) linked via bridges between amino acid side chains. In S. aureus, the bridge is (Gly)5-D-Ala between lysines. The cross-linking is catalyzed by a transpeptidase, the enzyme that penicillins and cephalosporins inhibit.
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 53-2A). The peptidoglycan is composed of glycan chains, which are linear strands of 2 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 transpeptidation reaction that occurs outside the cell membrane (Figure 53-2B). The β-lactam antibiotics inhibit this last step in peptidoglycan synthesis (see Figure 53-1), presumably by acylating the transpeptidase via cleavage of the —CO—N— bond of the β-lactam ring. There are additional, related targets for the actions of penicillins and cephalosporins; these are collectively termed PBPs. The transpeptidase responsible for synthesis of the peptidoglycan is 1 of these PBPs. The lethality of penicillin for bacteria appears to involve both lytic and nonlytic mechanisms.
A. Structure and composition of gram-positive and gram-negative cell walls. (From Figure 4-11, p 83 of TORTORA, GERALD, MICROBIOLOGY: INTRODUCTION, 3rd Edition, © 1989. Reprinted by permission of Pearson Education, Inc., Upper Saddle River, NJ.) B. Penicillin binding protein 2 (PBP2) from S. aureus. PBP2 has 2 enzymatic activities that are crucial to synthesis of the peptidoglycan layers of bacterial cell walls: a transpeptidase (TP) that cross-links amino acid side chains, and a glycosyltransferase (GT) that links ...
Pop-up div Successfully Displayed
This div only appears when the trigger link is hovered over.
Otherwise it is hidden from view.