A qnr-plasmid allows aminoglycosides to induce SOS in Escherichia coli

eLife

David Skurnik¹  Fethi Bedioui²  Sophie Griveau²  Gerald B Pier³  Christophe de Champs⁴  Thomas Guillard⁴  Anaëlle Muggeo⁴  Anamaria Babosan⁵  Sophie Moussalih⁵  Didier Mazel⁶  Zeynep Baharoglu⁶  Sébastien Vergnolle⁷  Thomas Jové⁸  Marie-Cécile Ploy⁸ 

[1] Assistance Publique-Hôpitaux de Paris, Department of Clinical Microbiology, Necker-Enfants Malades University Hospital, Université de Paris, 75015 Paris, France. INSERM U1151-Equipe 1, Institut Necker-Enfants Malades, Université de Paris, 75015 Paris, France. Division of Infectious Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA., Boston, United States;Chimie ParisTech, PSL Research University, CNRS, Institute of Chemistry for Life and Health Sciences, Paris, France;Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, United States;Inserm UMR-S 1250 P3Cell, SFR CAP-Santé, Université de Reims-Champagne-Ardenne, Reims, France. Laboratoire de Bactériologie-Virologie-Hygiène Hospitalière-Parasitologie- Mycologie, CHU Reims, Hôpital Robert Debré, Reims, France;Inserm UMR-S 1250 P3Cell, SFR CAP-Santé, Université de Reims-Champagne-Ardenne, Reims, France;Institut Pasteur, Unité Plasticité du Génome Bactérien, CNRS UMR3525, Paris, France;Laboratoire d’Hématologie, CH de Troyes, Troyes, France;Université de Limoges, Inserm, CHU Limoges, RESINFIT, UMR 1092, Limoges, France;

关键词: SOS;    Escherichia coli;    qnr;    aminoglycosides;    stress;    E. coli;   

DOI  :  10.7554/eLife.69511

来源: eLife Sciences Publications, Ltd

【 摘 要 】

The plasmid-mediated quinolone resistance (PMQR) genes have been shown to promote high-level bacterial resistance to fluoroquinolone antibiotics, potentially leading to clinical treatment failures. In Escherichia coli, sub-minimum inhibitory concentrations (sub-MICs) of the widely used fluoroquinolones are known to induce the SOS response. Interestingly, the expression of several PMQR qnr genes is controlled by the SOS master regulator, LexA. During the characterization of a small qnrD-plasmid carried in E. coli, we observed that the aminoglycosides become able to induce the SOS response in this species, thus leading to the elevated transcription of qnrD. Our findings show that the induction of the SOS response is due to nitric oxide (NO) accumulation in the presence of sub-MIC of aminoglycosides. We demonstrated that the NO accumulation is driven by two plasmid genes, ORF3 and ORF4, whose products act at two levels. ORF3 encodes a putative flavin adenine dinucleotide (FAD)-binding oxidoreductase which helps NO synthesis, while ORF4 codes for a putative fumarate and nitrate reductase (FNR)-type transcription factor, related to an O2-responsive regulator of hmp expression, able to repress the Hmp-mediated NO detoxification pathway of E. coli. Thus, this discovery, that other major classes of antibiotics may induce the SOS response could have worthwhile implications for antibiotic stewardship efforts in preventing the emergence of resistance.

【 授权许可】

CC BY