title: Subinhibitory Concentrations of Ciprofloxacin Enhance Antimicrobial Resistance and Pathogenicity of Enterococcus faecium.
abstract: Enterococcus faeciumhas 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 occurin 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 ofE. faeciumTranscriptomic analysis was performed by RNA sequencing (RNA-seq) (HiSeq 2500; Illumina) using thevanB-positive reference strainE. faeciumAus0004 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 theE. faeciumgenome was altered. Among upregulated genes, EFAU004_02294 (fold change, 14.3) encoded a protein (Qnr ofE. faecium[EfmQnr]) homologue of Qnr proteins involved in quinolone resistance in Gram-negative bacilli. Its implication in intrinsic and adaptive fluoroquinolone (FQ) resistance inE. faeciumwas 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 ofE. faeciumthat resides in the gut of patients receiving fluoroquinolone therapy.
authors.affiliation: University of Caen Normandie, EA4655 (Team Antibioresistance), Caen, France.
authors.forename: Clara
authors.initials: C
authors.lastname: Sinel
authors.affiliation: Catholic University of Sacred Heart, Institute of Microbiology, Rome, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Cacaci
authors.affiliation: University of Caen Normandie, IUT (Department STID), Caen, France.
authors.forename: Pierrick
authors.initials: P
authors.lastname: Meignen
authors.affiliation: University of Caen Normandie, EA4655 (Team Antibioresistance), Caen, France.|Caen University Hospital, Department of Clinical Microbiology, Caen, France.|National Reference Center for Antimicrobial Resistance (Lab Enterococci), Caen, France.
authors.forename: François
authors.initials: F
authors.lastname: Guérin
authors.affiliation: 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.
authors.forename: Bryan W
authors.initials: BW
authors.lastname: Davies
authors.affiliation: Catholic University of Sacred Heart, Institute of Microbiology, Rome, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Sanguinetti
authors.affiliation: University of Caen Normandie, EA4655 (Team Antibioresistance), Caen, France.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Giard
authors.affiliation: University of Caen Normandie, EA4655 (Team Antibioresistance), Caen, France vincent.cattoir@chu-rennes.fr.|Caen University Hospital, Department of Clinical Microbiology, Caen, France.|National Reference Center for Antimicrobial Resistance (Lab Enterococci), Caen, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Cattoir
mesh_terms: D018829:Adhesins, Bacterial / Q000235:genetics*; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics*; D002939:Ciprofloxacin / Q000494:pharmacology*; D003094:Collagen / Q000378:metabolism; D024881:Drug Resistance, Bacterial / Q000187:drug effects* / Q000235:genetics; D016984:Enterococcus faecium / Q000187:drug effects* / Q000235:genetics; D016680:Genome, Bacterial / Q000235:genetics; D016908:Gram-Positive Bacterial Infections / Q000188:drug therapy / Q000382:microbiology; D006801:Humans; D008826:Microbial Sensitivity Tests; D015363:Quinolones / Q000494:pharmacology; D059467:Transcriptome / Q000235:genetics
chemical_list: C473793:Acm protein, Enterococcus faecium; D018829:Adhesins, Bacterial; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; C000625761:Qnr protein, Enterococcus faecium; D015363:Quinolones; D002939:Ciprofloxacin; D003094:Collagen
keywords: Acm; E. faecium; Qnr; RNA-seq; VRE; fluoroquinolones; transcriptome