Invited Speaker 14th Lorne Infection and Immunity 2024

How cell wall targeting antibiotics kill bacteria (#3)

Yoshikazu Kawai 1 , Yousef Dashti 1 , Jeff Errington 1
  1. University of Sydney, Eveleigh, Sydney, NSW, Australia

Inhibition of bacterial cell wall synthesis by antibiotics such as β-lactams is traditionally thought to kill cells by explosive lysis, through loss of cell wall integrity. However, Gram positive bacteria generally do not die by this mechanism. Rather, recent studies have suggested that cell wall inhibitors work by perturbing central carbon metabolism, contributing to death via oxidative damage. Genetic dissection of these effects in Bacillus subtilis, has identified the key metabolic steps that stimulate the generation of damaging reactive oxygen species through cellular respiration. We screened a collection of natural product extracts for the ability to protect cells from killing under certain cell-wall perturbing conditions. We purified a highly protective factor, which turned out to be a siderophore-like compound, mirubactin C, suggesting a critical role for iron homeostasis in the oxidative damage-mediated lethal effects. We showed that the compound uncouples changes in cell morphology normally associated with cell death, from lysis as usually judged by a phase pale microscopic appearance. The results of biochemical and imaging experiments identify membrane damage by lipid peroxidation as a major factor in killing by cell-wall targeting antibiotics. These findings have important implications for the development of new antibiotics and antibiotic combinations.


  1. Kepplinger B, Wen X, Tyler AR, Kim B-Y, Brown J, Banks P, Dashti Y, Mackenzie ES, Wills C, Kawai Y, Waldron KJ, Allenby NEE, Wu LJ, Hall MJ, Errington J. (2022) Mirubactin C rescues the lethal effect of cell wall biosynthesis mutations in Bacillus subtilis. Frontiers Microbiol. 13:1004737.
  2. Kawai Y, Kawai M, Mackenzie ES, Dashti Y, Kepplinger B, Waldron KJ, Errington J. (2023) On the mechanisms of lysis triggered by perturbations of bacterial cell wall biosynthesis. Nature Communications 14(1):4123.