A Mutation of the RNA Polymerase beta ' Subunit (rpoC) Confers Cephalosporin Resistance in Bacillus subtilis

作者：Lee Yong Heon; Nam Ki Hyun; Helmann John D^*

来源：Antimicrobial Agents and Chemotherapy, 2013, 57(1): 56-65.

DOI：10.1128/AAC.01449-12

In bacteria, mutations affecting the major catalytic subunits of RNA polymerase (encoded by rpoB and rpoC) emerge in response to a variety of selective pressures. Here we isolated a Bacillus subtilis strain with high-level resistance to cefuroxime (CEF). Whole-genome resequencing revealed only one missense mutation affecting an invariant residue in close proximity to the C-terminal DNA-binding domain of RpoC (G1122D). Genetic reconstruction experiments demonstrate that this substitution is sufficient to confer CEF resistance. The G1122D mutation leads to elevated expression of stress-responsive regulons, including those of extracytoplasmic ECF) sigma factors (sigma(M), sigma(W), and sigma(X)) and the general stress sigma factor (sigma(B)). The increased CEF resistance of the rpoC(G1122D) strain is lost in the sigM rpoC(G1122D) double mutant, consistent with a major role for sigma(M) in CEF resistance. However, a sigM mutant is very sensitive to CEF, and this sensitivity is still reduced by the G1122D mutation, suggesting that other regulatory effects are also important. Indeed, the ability of the G1122D mutation to increase CEF resistance is further reduced in a triple mutant strain lacking three ECF sigma factors (sigma(M), sigma(W), and sigma(X)), which are known from prior studies to control overlapping sets of genes. Collectively, our findings highlight the ability of mutations in RNA polymerase to confer antibiotic resistance by affecting the activity of alternative sigma factors that control cell envelope stress-responsive regulons.

• 出版日期2013-1