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

Inhibition of bacterial cell wall synthesis by & beta;-lactam antibiotics results in a loss of cell wall integrity, but cells die via a combination of downstream events involving metabolic perturbations and oxidative damage. Here, Kawai et al. identify key enzymatic steps that stimulate the generation of reactive oxygen species and highlight the role of iron homeostasis in the lethal effects mediated by oxidative damage. Inhibition of bacterial cell wall synthesis by antibiotics such as & beta;-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. Here, we genetically dissect this connection in Bacillus subtilis perturbed for cell wall synthesis, and identify key enzymatic steps in upstream and downstream pathways that stimulate the generation of reactive oxygen species through cellular respiration. Our results also reveal the critical role of iron homeostasis for the oxidative damage-mediated lethal effects. We show that protection of cells from oxygen radicals via a recently discovered siderophore-like compound uncouples 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 closely associated with lipid peroxidation.