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Antimicrob Agents Chemother. 2017 Apr 24;61(5). pii: e02763-16. doi: 10.1128/AAC.02763-16. Print 2017 May.

Subinhibitory Concentrations of Ciprofloxacin Enhance Antimicrobial Resistance and Pathogenicity of Enterococcus faecium.

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University of Caen Normandie, EA4655 (Team Antibioresistance), Caen, France.
Catholic University of Sacred Heart, Institute of Microbiology, Rome, Italy.
University of Caen Normandie, IUT (Department STID), Caen, France.
Caen University Hospital, Department of Clinical Microbiology, Caen, France.
National Reference Center for Antimicrobial Resistance (Lab Enterococci), Caen, France.
Department of Molecular Biosciences, University of Texas at Austin, Austin, Texas, USA.
Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, Texas, USA.
University of Caen Normandie, EA4655 (Team Antibioresistance), Caen, France


Enterococcus faecium has emerged as a major opportunistic pathogen for 2 decades with the spread of hospital-adapted multidrug-resistant clones. As members of the intestinal microbiota, they are subjected to numerous bacterial stresses, including antibiotics at subinhibitory concentrations (SICs). Since fluoroquinolones are extensively prescribed, SICs are very likely to occur in vivo, with potential effects on bacterial metabolism with subsequent modulation of opportunistic traits. The aim of this study was to evaluate globally the impact of SICs of ciprofloxacin on antimicrobial resistance and pathogenicity of E. faecium Transcriptomic analysis was performed by RNA sequencing (RNA-seq) (HiSeq 2500; Illumina) using the vanB-positive reference strain E. faecium Aus0004 in the absence or presence of ciprofloxacin SIC (0.38 mg/liter, i.e., 1/8 of the MIC). Several genetic and phenotypic tests were used for validation. In the presence of ciprofloxacin SIC, 196 genes were significantly induced, whereas 286 genes were significantly repressed, meaning that 16.8% of the E. faecium genome was altered. Among upregulated genes, EFAU004_02294 (fold change, 14.3) encoded a protein (Qnr of E. faecium [EfmQnr]) homologue of Qnr proteins involved in quinolone resistance in Gram-negative bacilli. Its implication in intrinsic and adaptive fluoroquinolone (FQ) resistance in E. faecium was experimentally ascertained. Moreover, EFAU004_02292, coding for the collagen adhesin Acm, was also induced by the SIC of ciprofloxacin (fold change, 8.2), and higher adhesion capabilities were demonstrated phenotypically. Both EfmQnr and Acm determinants may play an important role in the transition from a commensal to a pathogenic state of E. faecium that resides in the gut of patients receiving fluoroquinolone therapy.


Acm; E. faecium; Qnr; RNA-seq; VRE; fluoroquinolones; transcriptome

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