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Analysis of the role of Bacillus subtilis σ M in β‐lactam resistance reveals an essential role for c‐di‐AMP in peptidoglycan homeostasis
Author(s) -
Luo Yun,
Helmann John D.
Publication year - 2012
Publication title -
molecular microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.857
H-Index - 247
eISSN - 1365-2958
pISSN - 0950-382X
DOI - 10.1111/j.1365-2958.2011.07953.x
Subject(s) - bacillus subtilis , peptidoglycan , biology , homeostasis , microbiology and biotechnology , bacteria , genetics
Summary The Bacillus subtilis extracytoplasmic function (ECF) σ factor σ M is inducible by, and confers resistance to, several cell envelope‐acting antibiotics. Here, we demonstrate that σ M is responsible for intrinsic β‐lactam resistance, with σ X playing a secondary role. Activation of σ M upregulates several cell wall biosynthetic enzymes including one, PBP1, shown here to be a target for the beta‐lactam cefuroxime. However, σ M still plays a major role in cefuroxime resistance even in cells lacking PBP1. To better define the role of σ M 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, σ M 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.