Constructing and Deconstructing the Bacterial Cell Wall

The history of modern medicine cannot be written apart from the history of the antibiotics. Antibiotics are cytotoxic secondary metabolites that are isolated from Nature. The antibacterial antibiotics disproportionately target bacterial protein structure that is distinct from eukaryotic protein structure, notably within the ribosome and within the pathways for bacterial cell-wall biosynthesis (for which there is not a eukaryotic counterpart). This review focuses on a pre-eminent class of antibiotics-the β-lactams, exemplified by the penicillins and cephalosporins-from the perspective of the evolving mechanisms for bacterial resistance. The mechanism of action of the β-lactams is bacterial cell-wall destruction. In the monoderm (single membrane, Gram-positive staining) pathogen Staphylococcus aureus the dominant resistance mechanism is expression of a β-lactam-unreactive transpeptidase enzyme that functions in cell-wall construction. In the diderm (dual membrane, Gram-negative staining) pathogen Pseudomonas aeruginosa a dominant resistance mechanism (among several) is expression of a hydrolytic enzyme that destroys the critical β-lactam ring of the antibiotic. The key sensing mechanism used by P. aeruginosa is monitoring the molecular difference between cell-wall construction and cell-wall deconstruction. In both bacteria, the resistance pathways are manifested only when the bacteria detect the presence of β-lactams. This review summarizes how the β-lactams are sensed and how the resistance mechanisms are manifested, with the expectation that preventing these processes will be critical to future chemotherapeutic control of multidrug resistant bacteria.