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      Prevalence of mcr-type genes among colistin-resistant Enterobacteriaceae collected in 2014-2016 as part of the INFORM global surveillance program

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          Abstract

          A set of 908 clinically derived colistin-resistant Enterobacteriaeae isolates collected worldwide in 2014–2016 were screened for the presence of the plasmid-borne mcr-1, mcr-2, mcr-3, mcr-4 and mcr-5 genes. In total 3.2% (29/908) of the collection were positive for mcr, including 27 Escherichia coli, 1 Klebsiella pneumoniae and 1 Enterobacter cloacae. Twenty-four isolates possessed genes from the mcr-1 family, including the original mcr-1 (n = 22), as well as mcr-1.2 (n = 1) and mcr-1.5 (n = 1), which each differ from mcr-1 by encoding single amino acid variations. Genes from the mcr-3 family were found in isolates from Thailand, including mcr-3.1 (n = 3) and mcr-3.2 (n = 1). An E. coli isolated from a patient with a urinary tract infection in Colombia contained the recently discovered mcr-5. The full colistin-resistant collection was tested against a panel of antimicrobial agents with ceftazidime-avibactam and tigecycline exhibiting the highest activity.

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          Novel Plasmid-Mediated Colistin Resistance Gene mcr-3 in Escherichia coli

          ABSTRACT The mobile colistin resistance gene mcr-1 has attracted global attention, as it heralds the breach of polymyxins, one of the last-resort antibiotics for the treatment of severe clinical infections caused by multidrug-resistant Gram-negative bacteria. To date, six slightly different variants of mcr-1, and a second mobile colistin resistance gene, mcr-2, have been reported or annotated in the GenBank database. Here, we characterized a third mobile colistin resistance gene, mcr-3. The gene coexisted with 18 additional resistance determinants in the 261-kb IncHI2-type plasmid pWJ1 from porcine Escherichia coli. mcr-3 showed 45.0% and 47.0% nucleotide sequence identity to mcr-1 and mcr-2, respectively, while the deduced amino acid sequence of MCR-3 showed 99.8 to 100% and 75.6 to 94.8% identity to phosphoethanolamine transferases found in other Enterobacteriaceae species and in 10 Aeromonas species, respectively. pWJ1 was mobilized to an E. coli recipient by conjugation and contained a plasmid backbone similar to those of other mcr-1-carrying plasmids, such as pHNSHP45-2 from the original mcr-1-harboring E. coli strain. Moreover, a truncated transposon element, TnAs2, which was characterized only in Aeromonas salmonicida, was located upstream of mcr-3 in pWJ1. This ΔTnAs2-mcr-3 element was also identified in a shotgun genome sequence of a porcine E. coli isolate from Malaysia, a human Klebsiella pneumoniae isolate from Thailand, and a human Salmonella enterica serovar Typhimurium isolate from the United States. These results suggest the likelihood of a wide dissemination of the novel mobile colistin resistance gene mcr-3 among Enterobacteriaceae and aeromonads; the latter may act as a potential reservoir for mcr-3.
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            Identification of a novel transposon-associated phosphoethanolamine transferase gene, mcr-5, conferring colistin resistance in d-tartrate fermenting Salmonella enterica subsp. enterica serovar Paratyphi B.

            Plasmid-mediated mobilized colistin resistance is currently known to be caused by phosphoethanolamine transferases termed MCR-1, MCR-2, MCR-3 and MCR-4. However, this study focuses on the dissection of a novel resistance mechanism in mcr-1-, mcr-2- and mcr-3-negative d-tartrate fermenting Salmonella enterica subsp. enterica serovar Paratyphi B (Salmonella Paratyphi B dTa+) isolates with colistin MIC values >2 mg/L.
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              Novel plasmid-mediated colistin resistance mcr-4 gene in Salmonella and Escherichia coli, Italy 2013, Spain and Belgium, 2015 to 2016

              A novel mcr colistin resistance gene was identified in a strain of Salmonella enterica, monophasic variant of serovar Typhimurium (4,5,12:i:- ), isolated from a pig at slaughter in Italy in 2013, and in Escherichia coli strains collected during routine diagnostic of post-weaning diarrhoea in pigs from Spain and Belgium in 2015 and 2016. Immediate implementation of mcr-screening including this novel gene variant is required for Salmonella and E. coli from humans and food-producing animals in Europe.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: Writing – original draftRole: Writing – review & editing
                Role: Formal analysisRole: InvestigationRole: Methodology
                Role: Conceptualization
                Role: Funding acquisition
                Role: Conceptualization
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                2 April 2018
                2018
                : 13
                : 4
                : e0195281
                Affiliations
                [1 ] International Health Management Associates, Schaumburg, Illinois, United States of America
                [2 ] AstraZeneca Pharmaceuticals, Waltham, Massachusetts, United States of America
                Cornell University, UNITED STATES
                Author notes

                Competing Interests: All work was performed at IHMA and sponsored by AstraZeneca Pharmaceuticals, LP, which also included compensation fees for manuscript preparation. AstraZeneca’s rights to ceftazidime-avibactam were acquired by Pfizer in December 2016. G.S. was an employee of and shareholder in AstraZeneca Pharmaceuticals at the time of the study, and is currently an employee of Pfizer. M.W., M.E., D.S. and K.K. are employees of IHMA which received funding from AstraZeneca for the conduct of the study and development of this manuscript. None of the IHMA authors have any personal financial interest in the study sponsor (AstraZeneca Pharmaceuticals, LP) to disclose. This does not alter our adherence to all PLOS ONE policies on sharing data and materials.

                [¤]

                Current address: Pfizer, Inc., Groton, Connecticut, United States of America

                Author information
                http://orcid.org/0000-0001-7356-1851
                Article
                PONE-D-17-43607
                10.1371/journal.pone.0195281
                5880376
                29608599
                232e92ad-87ab-4bed-89e7-1faa5058ea1d
                © 2018 Wise et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 13 December 2017
                : 19 March 2018
                Page count
                Figures: 0, Tables: 2, Pages: 8
                Funding
                All work was performed at IHMA and sponsored by AstraZeneca Pharmaceuticals, LP, which also included compensation fees for manuscript preparation. AstraZeneca’s rights to ceftazidime-avibactam were acquired by Pfizer in December 2016.
                Categories
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                Research and Analysis Methods
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