title: AsrR is an oxidative stress sensing regulator modulating Enterococcus faecium opportunistic traits, antimicrobial resistance, and pathogenicity.
abstract: Oxidative stress serves as an important host/environmental signal that triggers a wide range of responses in microorganisms. Here, we identified an oxidative stress sensor and response regulator in the important multidrug-resistant nosocomial pathogen Enterococcus faecium belonging to the MarR family and called AsrR (antibiotic and stress response regulator). The AsrR regulator used cysteine oxidation to sense the hydrogen peroxide which results in its dissociation to promoter DNA. Transcriptome analysis showed that the AsrR regulon was composed of 181 genes, including representing functionally diverse groups involved in pathogenesis, antibiotic and antimicrobial peptide resistance, oxidative stress, and adaptive responses. Consistent with the upregulated expression of the pbp5 gene, encoding a low-affinity penicillin-binding protein, the asrR null mutant was found to be more resistant to β-lactam antibiotics. Deletion of asrR markedly decreased the bactericidal activity of ampicillin and vancomycin, which are both commonly used to treat infections due to enterococci, and also led to over-expression of two major adhesins, acm and ecbA, which resulted in enhanced in vitro adhesion to human intestinal cells. Additional pathogenic traits were also reinforced in the asrR null mutant including greater capacity than the parental strain to form biofilm in vitro and greater persistance in Galleria mellonella colonization and mouse systemic infection models. Despite overexpression of oxidative stress-response genes, deletion of asrR was associated with a decreased oxidative stress resistance in vitro, which correlated with a reduced resistance to phagocytic killing by murine macrophages. Interestingly, both strains showed similar amounts of intracellular reactive oxygen species. Finally, we observed a mutator phenotype and enhanced DNA transfer frequencies in the asrR deleted strain. These data indicate that AsrR plays a major role in antimicrobial resistance and adaptation for survival within the host, thereby contributes importantly to the opportunistic traits of E. faecium.
authors.affiliation: University of Caen Basse-Normandie, EA4655 (team "Antibioresistance"), Medical School, Caen, France.
authors.forename: François
authors.initials: F
authors.lastname: Lebreton
authors.forename: Willem
authors.initials: W
authors.lastname: van Schaik
authors.forename: Maurizio
authors.initials: M
authors.lastname: Sanguinetti
authors.forename: Brunella
authors.initials: B
authors.lastname: Posteraro
authors.forename: Riccardo
authors.initials: R
authors.lastname: Torelli
authors.forename: Florian
authors.initials: F
authors.lastname: Le Bras
authors.forename: Nicolas
authors.initials: N
authors.lastname: Verneuil
authors.forename: Xinglin
authors.initials: X
authors.lastname: Zhang
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Giard
authors.forename: Anne
authors.initials: A
authors.lastname: Dhalluin
authors.forename: Rob J L
authors.initials: RJ
authors.lastname: Willems
authors.forename: Roland
authors.initials: R
authors.lastname: Leclercq
authors.forename: Vincent
authors.initials: V
authors.lastname: Cattoir
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D016984:Enterococcus faecium / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D016908:Gram-Positive Bacterial Infections / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000378:metabolism / Q000382:microbiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016877:Oxidants / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D019655:Quantitative Trait, Heritable; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D018440:beta-Lactam Resistance; D047090:beta-Lactams / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D016877:Oxidants; D014157:Transcription Factors; D047090:beta-Lactams; D006861:Hydrogen Peroxide