Analysis of the role ofBacillus subtilisσMin β‐lactam resistance reveals an essential role for c‐di‐AMP in peptidoglycan homeostasis

Authors:
Open Access
Publisher website
Google Scholar
Abstract
Summary: TheBacillus subtilisextracytoplasmic function (ECF) σ factor σMis inducible by, and confers resistance to, several cell envelope‐acting antibiotics. Here, we demonstrate that σMis responsible for intrinsic β‐lactam resistance, with σXplaying a secondary role. Activation of σMupregulates several cell wall biosynthetic enzymes including one, PBP1, shown here to be a target for the beta‐lactam cefuroxime. However, σMstill plays a major role in cefuroxime resistance even in cells lacking PBP1. To better define the role of σMin β‐lactam resistance, we characterized suppressor mutations that restore cefuroxime resistance to asigMnull mutant. The most frequent suppressors inactivatedgdpP(yybT) which encodes a cyclic‐di‐AMP phosphodiesterase (PDE). Intriguingly, σMis a known activator ofdisAencoding one of three paralogous diadenylate cyclases (DAC). Overproduction of the GdpP PDE greatly sensitized cells to β‐lactam antibiotics. Conversely, genetic studies indicate that at least one DAC is required for growth with depletion leading to cell lysis. These findings support a model in which c‐di‐AMP is an essential signal molecule required for cell wall homeostasis. Other suppressors highlight the roles of ECF σ factors in counteracting the deleterious effects of autolysins and reactive oxygen species in β‐lactam‐treated cells.

This publication has 90 references indexed in Scilit: