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Analysis of the role of Bacillus subtilis
 σM in β‐lactam resistance reveals an essential role for c‐di‐AMP in peptidoglycan homeostasis

The Bacillus subtilis extracytoplasmic function (ECF) σ factor σM is inducible by, and confers resistance to, several cell envelope‐acting antibiotics. Here, we demonstrate that σM is responsible for intrinsic β‐lactam resistance, with σX playing a secondary role. Activation of σM upregulates several cell wall biosynthetic enzymes including one, PBP1, shown here to be a target for the beta‐lactam cefuroxime. However, σM still plays a major role in cefuroxime resistance even in cells lacking PBP1. To better define the role of σM in β‐lactam resistance, we characterized suppressor mutations that restore cefuroxime resistance to a sigM null mutant. The most frequent suppressors inactivated gdpP (yybT) which encodes a cyclic‐di‐AMP phosphodiesterase (PDE). Intriguingly, σM is a known activator of disA encoding 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.