title: Worldwide emergence of colistin resistance in Klebsiella pneumoniae from healthy humans and patients in Lao PDR, Thailand, Israel, Nigeria and France owing to inactivation of the PhoP/PhoQ regulator mgrB: an epidemiological and molecular study.
abstract: The emergence of colistin-resistant Klebsiella pneumoniae (CRKP) is a major public health concern worldwide. In this study, the prevalence and molecular basis of colistin resistance in CRKP isolated from healthy individuals and patients in Lao PDR, Thailand, Nigeria and France were investigated. Stool samples were screened by culture for the presence of colistin-resistant Klebsiella spp. Whole-genome sequence analysis was used to decipher the molecular mechanism of colistin resistance in a blaNDM-1-positive in vitro-selected CRKP mutant. PCR amplification and sequencing of the mgrB genetic environment was performed for all CRKP isolates as well as control colistin-susceptible K. pneumoniae (CSKP) isolates recovered from the same stools. A total of 869 stool samples were screened for colistin-resistant Klebsiella spp., yielding 32 CRKP and 2 colistin-resistant Klebsiella oxytoca. Comparative whole-genome sequence analysis revealed that an in vitro-selected CRKP mutant had an insertion sequence in its mgrB gene, as well as missense mutations in other selected clones. Of the 34 colistin-resistant Klebsiella spp. isolates, 14 (41.2%; 13 CRKP and 1 K. oxytoca) from the four countries also had various defects in their mgrB genes, but no such defects were found in the CSKP controls (P<10(-4)). Few mutations were observed in pmrAB compared with mgrB among the CRKP isolates. The worldwide emergence of CRKP is a major public health concern. Detection and surveillance of such strains are warranted to prevent an uncontrollable pandemic. Inactivation of the PhoP/PhoQ regulator gene mgrB is associated with ≥40% of colistin resistance among the CRKP isolates observed in this study.
authors.affiliation: Unité de recherche sur les maladies infectieuses et tropicales émergentes (URMITE), CNRS-IRD UMR 6236, Méditerranée Infection, Faculté de Médecine et de Pharmacie, Aix-Marseille-Université, Marseille, France.
authors.forename: Abiola Olumuyiwa
authors.initials: AO
authors.lastname: Olaitan
authors.affiliation: Unité de recherche sur les maladies infectieuses et tropicales émergentes (URMITE), CNRS-IRD UMR 6236, Méditerranée Infection, Faculté de Médecine et de Pharmacie, Aix-Marseille-Université, Marseille, France.
authors.forename: Seydina M
authors.initials: SM
authors.lastname: Diene
authors.affiliation: Laboratoire de Bactériologie, Institut de Biologie en santé - PBH, CHU, Angers, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Kempf
authors.affiliation: Unité de recherche sur les maladies infectieuses et tropicales émergentes (URMITE), CNRS-IRD UMR 6236, Méditerranée Infection, Faculté de Médecine et de Pharmacie, Aix-Marseille-Université, Marseille, France.
authors.forename: Meryem
authors.initials: M
authors.lastname: Berrazeg
authors.affiliation: Unité de recherche sur les maladies infectieuses et tropicales émergentes (URMITE), CNRS-IRD UMR 6236, Méditerranée Infection, Faculté de Médecine et de Pharmacie, Aix-Marseille-Université, Marseille, France.
authors.forename: Sofiane
authors.initials: S
authors.lastname: Bakour
authors.affiliation: Unité de recherche sur les maladies infectieuses et tropicales émergentes (URMITE), CNRS-IRD UMR 6236, Méditerranée Infection, Faculté de Médecine et de Pharmacie, Aix-Marseille-Université, Marseille, France.
authors.forename: Sushim Kumar
authors.initials: SK
authors.lastname: Gupta
authors.affiliation: National Institute of Health, Vientiane, Lao Democratic People's Republic.
authors.forename: Boupha
authors.initials: B
authors.lastname: Thongmalayvong
authors.affiliation: National Institute of Health, Vientiane, Lao Democratic People's Republic.
authors.forename: Kongsap
authors.initials: K
authors.lastname: Akkhavong
authors.affiliation: Centre d'Infectiologie Christophe Mérieux du Laos, Vientiane, Lao Democratic People's Republic.
authors.forename: Silaphet
authors.initials: S
authors.lastname: Somphavong
authors.affiliation: Centre d'Infectiologie Christophe Mérieux du Laos, Vientiane, Lao Democratic People's Republic.
authors.forename: Phimpha
authors.initials: P
authors.lastname: Paboriboune
authors.affiliation: Department of Helminthology, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Kittipong
authors.initials: K
authors.lastname: Chaisiri
authors.affiliation: Department of Helminthology, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Chalit
authors.initials: C
authors.lastname: Komalamisra
authors.affiliation: Environmental Microbiology and Biotechnology Laboratory, Department of Microbiology, University of Ibadan, Ibadan, Nigeria.
authors.forename: Olawale Olufemi
authors.initials: OO
authors.lastname: Adelowo
authors.affiliation: Environmental Microbiology and Biotechnology Laboratory, Department of Microbiology, University of Ibadan, Ibadan, Nigeria.
authors.forename: Obasola Ezekiel
authors.initials: OE
authors.lastname: Fagade
authors.affiliation: Environmental Microbiology and Biotechnology Laboratory, Department of Microbiology, University of Ibadan, Ibadan, Nigeria.
authors.forename: Omowunmi Abosede
authors.initials: OA
authors.lastname: Banjo
authors.affiliation: Bowen University Teaching Hospital, Ogbomosho, Nigeria.
authors.forename: Adeyeye James
authors.initials: AJ
authors.lastname: Oke
authors.affiliation: National Center for Infection Control, Ministry of Health, Israel.
authors.forename: Amos
authors.initials: A
authors.lastname: Adler
authors.affiliation: Microbiology and Immunology Laboratory, Shaare Zedek Medical Center, Jerusalem, Israel.
authors.forename: Marc Victor
authors.initials: MV
authors.lastname: Assous
authors.affiliation: Institut des Sciences de l'Évolution, CNRS-IRD-UM2, CC065, Université Montpellier 2, 34095 Montpellier cedex 05, France.
authors.forename: Serge
authors.initials: S
authors.lastname: Morand
authors.affiliation: Unité de recherche sur les maladies infectieuses et tropicales émergentes (URMITE), CNRS-IRD UMR 6236, Méditerranée Infection, Faculté de Médecine et de Pharmacie, Aix-Marseille-Université, Marseille, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Raoult
authors.affiliation: Unité de recherche sur les maladies infectieuses et tropicales émergentes (URMITE), CNRS-IRD UMR 6236, Méditerranée Infection, Faculté de Médecine et de Pharmacie, Aix-Marseille-Université, Marseille, France. Electronic address: jean-marc.rolain@univ-amu.fr.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Rolain
mesh_terms: D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics; D003091:Colistin / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial; D005243:Feces / Q000382:microbiology; D005602:France / Q000453:epidemiology; D016680:Genome, Bacterial / Q000235:genetics*; D006801:Humans; D007557:Israel / Q000453:epidemiology; D007710:Klebsiella Infections / Q000188:drug therapy / Q000453:epidemiology* / Q000382:microbiology; D007711:Klebsiella pneumoniae / Q000187:drug effects / Q000235:genetics* / Q000302:isolation & purification; D007812:Laos / Q000453:epidemiology; D008297:Male; D008969:Molecular Sequence Data; D009549:Nigeria / Q000453:epidemiology; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D013785:Thailand / Q000453:epidemiology
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; C079792:PhoQ protein, Bacteria; C061064:PhoP protein, Bacteria; D003091:Colistin
keywords: Antibiotic resistance; Colistin resistance; Genome analysis; Transposon; Two-component systems; mgrB gene