Transcriptional and Adaptive Responses of Enterococcus Faecium to the Antiseptic Chlorhexidine




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Enterococcus faecium and E. faecalis are Gram-positive cocci that naturally colonize the gastrointestinal tracts of humans and animals. However, they are opportunistic pathogens that are particularly associated with central line-associated bloodstream infections (CLABSIs), wound infections, bacteremia, and endocarditis. Chlorhexidine (CHX), a bisbiguanide cationic antiseptic, is routinely used for patient bathing in critical care units and in various infection control practices to reduce CLABSI occurrence. Enterococci are likely frequently exposed to inhibitory as well as sub-inhibitory levels of CHX as a result of colonization of patients bathed with CHX or use of CHX-impregnated catheters. However, there is a critical gap in knowledge about the evolutionary outcomes of CHX bathing on bacteria associated with CLABSIs. Also, more generally, the mechanisms by which enterococci detect and respond to cell surface stress are poorly understood. The goal of my research is to investigate how vancomycin-resistant E. faecium detect and respond to CHX using RNA sequencing. In this dissertation, I describe the global transcriptional responses of E. faecium to CHX at the minimum inhibitory concentration. I find that CHX exposure induces expression of genes related to vancomycin and daptomycin (DAP) resistance, as well as transport systems and genes associated with extra-cytoplasmic stress. Due to the clinical significance of the upregulation of antibiotic resistance genes by a routinely used antiseptic, I use molecular and genetic approaches to understand the mechanism of induction of vancomycin resistance genes. In addition, I investigate evolutionary outcomes of CHX exposure on E. faecium utilizing in vitro serial passage experiments. I find that the bacterial populations with reduced susceptibility to CHX also have a significantly higher number of DAP-resistant mutants. I utilize whole-genome sequencing to investigate the mechanistic basis of CHX-induced daptomycin resistance in E. faecium. The findings of my dissertation have important clinical implications. Exposure to sub-inhibitory CHX can prime the enterococci for subsequent vancomycin exposure and impact treatment outcomes. If routine use of CHX can select for mutants with reduced susceptibility to CHX as well as cell surface-targeting antibiotics like DAP, this can contribute to treatment failures. Overall, the results of the dissertation highlight the importance of monitoring the effects of CHX exposure on E. faecium in healthcare settings.



Enterococcus faecalis, Chlorhexidine, Vancomycin, Gastrointestinal system, Drug resistance in microorganisms


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