Analysis of the role of Bacillus subtilis sigma(M) in beta-lactam resistance reveals an essential role for c-di-AMP in peptidoglycan homeostasis.

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Luo Y, Helmann JD

Analysis of the role of Bacillus subtilis sigma(M) in beta-lactam resistance reveals an essential role for c-di-AMP in peptidoglycan homeostasis.

Mol Microbiol. 2012 Feb;83(3):623-39. doi: 10.1111/j.1365-2958.2011.07953.x. Epub 2012 Jan 4.

PubMed ID
22211522 [ View in PubMed
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Abstract

The Bacillus subtilis extracytoplasmic function (ECF) sigma factor sigma(M) is inducible by, and confers resistance to, several cell envelope-acting antibiotics. Here, we demonstrate that sigma(M) is responsible for intrinsic beta-lactam resistance, with sigma(X) playing a secondary role. Activation of sigma(M) upregulates several cell wall biosynthetic enzymes including one, PBP1, shown here to be a target for the beta-lactam cefuroxime. However, sigma(M) still plays a major role in cefuroxime resistance even in cells lacking PBP1. To better define the role of sigma(M) in beta-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, sigma(M) is a known activator of disA encoding one of three paralogous diadenylate cyclases (DAC). Overproduction of the GdpP PDE greatly sensitized cells to beta-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 sigma factors in counteracting the deleterious effects of autolysins and reactive oxygen species in beta-lactam-treated cells.

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