title: Chromosomal Amplification of the blaOXA-58 Carbapenemase Gene in a Proteus mirabilis Clinical Isolate.
abstract: Horizontal gene transfer may occur between distantly related bacteria, thus leading to genetic plasticity and in some cases to acquisition of novel resistance traits. Proteus mirabilis is an enterobacterial species responsible for human infections that may express various acquired β-lactam resistance genes, including different classes of carbapenemase genes. Here we report a Proteus mirabilis clinical isolate (strain 1091) displaying resistance to penicillin, including temocillin, together with reduced susceptibility to carbapenems and susceptibility to expanded-spectrum cephalosporins. Using biochemical tests, significant carbapenem hydrolysis was detected in P. mirabilis 1091. Since PCR failed to detect acquired carbapenemase genes commonly found in Enterobacteriaceae, we used a whole-genome sequencing approach that revealed the presence of blaOXA-58class D carbapenemase gene, so far identified only in Acinetobacter species. This gene was located on a 3.1-kb element coharboring a blaAmpC-like gene. Remarkably, these two genes were bracketed by putative XerC-XerD binding sites and inserted at a XerC-XerD site located between the terminase-like small- and large-subunit genes of a bacteriophage. Increased expression of the two bla genes resulted from a 6-time tandem amplification of the element as revealed by Southern blotting. This is the first isolation of a clinical P. mirabilis strain producing OXA-58, a class D carbapenemase, and the first description of a XerC-XerD-dependent insertion of antibiotic resistance genes within a bacteriophage. This study revealed a new role for the XerC-XerD recombinase in bacteriophage biology.
authors.affiliation: EA7361, Université Paris-Sud, Université Paris-Saclay, LabEx Lermit, Bacteriology-Hygiene Unit, APHP, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.|Associated French National Reference Center for Antibiotic Resistance: Carbapenemase-Producing Enterobacteriaceae, Le Kremlin-Bicêtre, France.|Ecology and Evolution of Resistance to Antibiotics Unit, Institut Pasteur-APHP-Université Paris Sud, Paris, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Girlich
authors.affiliation: EA7361, Université Paris-Sud, Université Paris-Saclay, LabEx Lermit, Bacteriology-Hygiene Unit, APHP, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.|Associated French National Reference Center for Antibiotic Resistance: Carbapenemase-Producing Enterobacteriaceae, Le Kremlin-Bicêtre, France.|Ecology and Evolution of Resistance to Antibiotics Unit, Institut Pasteur-APHP-Université Paris Sud, Paris, France.
authors.forename: Rémy A
authors.identifier: 0000-0002-2307-3232
authors.initials: RA
authors.lastname: Bonnin
authors.affiliation: Belgian National Reference Laboratory for Monitoring of Antimicrobial Resistance in Gram-Negative Bacteria, Yvoir, Belgium.|CHU UCL Namur, Yvoir, Belgium.
authors.forename: Pierre
authors.initials: P
authors.lastname: Bogaerts
authors.affiliation: CHU UCL Namur, Yvoir, Belgium.
authors.forename: Morgane
authors.initials: M
authors.lastname: De Laveleye
authors.affiliation: Belgian National Reference Laboratory for Monitoring of Antimicrobial Resistance in Gram-Negative Bacteria, Yvoir, Belgium.|CHU UCL Namur, Yvoir, Belgium.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Huang
authors.affiliation: EA7361, Université Paris-Sud, Université Paris-Saclay, LabEx Lermit, Bacteriology-Hygiene Unit, APHP, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.|Associated French National Reference Center for Antibiotic Resistance: Carbapenemase-Producing Enterobacteriaceae, Le Kremlin-Bicêtre, France.|Ecology and Evolution of Resistance to Antibiotics Unit, Institut Pasteur-APHP-Université Paris Sud, Paris, France.
authors.forename: Laurent
authors.identifier: 0000-0001-6596-7384
authors.initials: L
authors.lastname: Dortet
authors.affiliation: Ecology and Evolution of Resistance to Antibiotics Unit, Institut Pasteur-APHP-Université Paris Sud, Paris, France pglaser@pasteur.fr thierry.naas@bct.aphp.fr.|CNRS UMR3525, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Glaser
authors.affiliation: Belgian National Reference Laboratory for Monitoring of Antimicrobial Resistance in Gram-Negative Bacteria, Yvoir, Belgium.|CHU UCL Namur, Yvoir, Belgium.
authors.forename: Youri
authors.initials: Y
authors.lastname: Glupczynski
authors.affiliation: EA7361, Université Paris-Sud, Université Paris-Saclay, LabEx Lermit, Bacteriology-Hygiene Unit, APHP, Hôpital Bicêtre, Le Kremlin-Bicêtre, France pglaser@pasteur.fr thierry.naas@bct.aphp.fr.|Associated French National Reference Center for Antibiotic Resistance: Carbapenemase-Producing Enterobacteriaceae, Le Kremlin-Bicêtre, France.|Ecology and Evolution of Resistance to Antibiotics Unit, Institut Pasteur-APHP-Université Paris Sud, Paris, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Naas
mesh_terms: D000328:Adult; D001426:Bacterial Proteins / Q000235:genetics* / Q000378:metabolism; D001665:Binding Sites; D002876:Chromosomes, Bacterial; D024881:Drug Resistance, Bacterial / Q000235:genetics; D004926:Escherichia coli / Q000235:genetics; D029968:Escherichia coli Proteins / Q000235:genetics / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial; D006801:Humans; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D008297:Male; D008826:Microbial Sensitivity Tests; D005810:Multigene Family; D039002:Prophages / Q000235:genetics*; D011512:Proteus Infections / Q000188:drug therapy / Q000209:etiology* / Q000382:microbiology; D011513:Proteus mirabilis / Q000187:drug effects / Q000235:genetics* / Q000302:isolation & purification; D001618:beta-Lactamases / Q000235:genetics*
chemical_list: D001426:Bacterial Proteins; D029968:Escherichia coli Proteins; C473360:XerC protein, E coli; D019426:Integrases; C473361:XerD protein, E coli; D001618:beta-Lactamases; C063912:carbapenemase
keywords: Acinetobacter baumannii; OXA-58; Proteus mirabilis; XerC-XerD recombinase; bacteriophage; carbapenems