On the mechanisms of lysis triggered by perturbations of bacterial cell wall biosynthesis

Abstract

Abstract Cell wall synthesis is an essential function for the growth of almost all bacteria, and a major target for our most effective antibiotics. Inhibition of cell wall synthesis by antibiotics such as β-lactams is thought to cause explosive lysis through loss of cell wall integrity. However, recent studies on a wide range of bacteria have suggested that these antibiotics also perturb central carbon metabolism, contributing to death via oxidative damage. We have genetically dissected this connection in Bacillus subtilis and identified key enzymatic steps in upstream and downstream pathways that stimulate the generation of reactive oxygen species (ROS) through cellular respiration. Our results also reveal the critical role of iron homeostasis for the ROS-mediated lethal effects, through iron-dependent enhancement of lipid peroxidation when cell wall synthesis is perturbed. Unexpectedly, we found that protection of cells from ROS via a recently discovered siderophore-like compound uncoupled changes in cell morphology normally associated with cell death, from lysis as usually judged by a phase pale microscopic appearance. Phase paling appears to be specifically associated with lipid peroxidation, presumably the result of membrane destabilization. Finally, we provide a new view of the differentiated roles of the widely conserved Rod and aPBP mechanisms of bacterial cell wall synthesis.