PT  - JOURNAL ARTICLE
AU  - Pooja Bhardwaj
AU  - Amrita Hans
AU  - Kinnari Ruikar
AU  - Ziqiang Guan
AU  - Kelli L. Palmer
TI  - Reduced chlorhexidine and daptomycin susceptibility arises in vancomycin-resistant <em>Enterococcus faecium</em> after serial chlorhexidine exposure
AID  - 10.1101/148809
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 148809
4099  - http://biorxiv.org/content/early/2017/06/13/148809.short
4100  - http://biorxiv.org/content/early/2017/06/13/148809.full
AB  - Vancomycin-resistant Enterococcus faecium (VREfm) are critical public health concerns because they are among the leading causes of hospital-acquired bloodstream infections. Chlorhexidine (CHX) is a bisbiguanide cationic antiseptic that is routinely used for patient bathing and other infection control practices. VREfm are likely frequently exposed to CHX; however, the long-term effects of CHX exposure have not been studied in enterococci. In this study, we serially exposed VREfm to increasing concentrations of CHX for a period of 21 days in two independent experimental evolution trials. Reduced CHX susceptibility emerged (4-fold shift in CHX MIC). Sub-populations with reduced daptomycin (DAP) susceptibility were detected, which were further analyzed by genome sequencing and lipidomic analysis. Across the trials, we identified adaptive changes in genes with predicted or experimentally confirmed roles in chlorhexidine susceptibility (efrE), global nutritional stress response (relA), nucleotide metabolism (cmk), phosphate acquisition (phoU), and glycolipid biosynthesis (bgsB), among others. Moreover, significant alterations in membrane phospholipids were identified. Our results are clinically significant because they identify a link between serial sub-inhibitory CHX exposure and reduced DAP susceptibility. In addition, the CHX-induced genetic and lipidomic changes described in this study offer new insights into the mechanisms underlying the emergence of antibiotic resistance in VREfm.