Requirement of the CroRS Two-Component System for Resistance to Cell Wall-Targeting Antimicrobials in Enterococcus faecium

Abstract

Enterococci are serious opportunistic pathogens that are resistant to many cell wall-targeting antibiotics. The CroRS two-component signaling system responds to antibiotic-mediated cell wall stress and is critical for resistance to cell wall-targeting antibiotics in <i>Enterococcus faecalis</i> Here, we identify and characterize an orthologous two-component system found in <i>Enterococcus faecium</i> that is functionally equivalent to the CroRS system of <i>E. faecalis</i> Deletion of <i>croRS</i> in <i>E. faecium</i> resulted in marked susceptibility to cell wall-targeting agents including cephalosporins and bacitracin, as well as moderate susceptibility to ampicillin and vancomycin. As in <i>E. faecalis</i>, exposure to bacitracin and vancomycin stimulates signaling through the CroRS system in <i>E. faecium</i> Moreover, the CroRS system is critical in <i>E. faecium</i> for enhanced beta-lactam resistance mediated by overexpression of Pbp5. Expression of a Pbp5 variant that confers enhanced beta-lactam resistance cannot overcome the requirement for CroRS function. Thus, the CroRS system is a conserved signaling system that responds to cell wall stress to promote intrinsic resistance to important cell wall-targeting antibiotics in clinically relevant enterococci.