Affiliation:
1. Department of Microbiology, Cornell University, Ithaca, New York, USA
2. Department of Biomedical Laboratory Science, Dongseo University, Busan, South Korea
Abstract
ABSTRACT
Combinations of glycopeptides and β-lactams exert synergistic antibacterial activity, but the evolutionary mechanisms driving resistance to both antibiotics remain largely unexplored. By repeated subculturing with increasing vancomycin (VAN) and cefuroxime (CEF) concentrations, we isolated an evolved strain of the model bacterium
Bacillus subtilis
with reduced susceptibility to both antibiotics. Whole-genome sequencing revealed point mutations in genes encoding the major σ factor of RNA polymerase (
sigA
), a cell shape-determining protein (
mreB
), and the ρ termination factor (
rho
). Genetic-reconstruction experiments demonstrated that the G-to-C substitution at position 336 encoded by
sigA
(
sigA
G336C
), in the domain that recognizes the −35 promoter region, is sufficient to reduce susceptibility to VAN and works cooperatively with the
rho
G56C
substitution to increase CEF resistance. Transcriptome analyses revealed that the
sigA
G336C
substitution has wide-ranging effects, including elevated expression of the general stress σ factor (σ
B
) regulon, which is required for CEF resistance, and decreased expression of the
glpTQ
genes, which leads to fosfomycin (FOS) resistance. Our findings suggest that mutations in the core transcriptional machinery may facilitate the evolution of resistance to multiple cell wall antibiotics.
Publisher
American Society for Microbiology
Subject
Molecular Biology,Microbiology
Cited by
23 articles.
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