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Identification of novel mobilized colistin resistance gene mcr-9 in a multidrug-resistant, colistin-susceptible salmonella enterica serotype typhimurium isolate


Carroll, Laura M; Gaballa, Ahmed; Guldimann, Claudia; Sullivan, Genevieve; Henderson, Lory O; Wiedmann, Martin (2019). Identification of novel mobilized colistin resistance gene mcr-9 in a multidrug-resistant, colistin-susceptible salmonella enterica serotype typhimurium isolate. mBio, 10(3):e00853-19.

Abstract

Mobilized colistin resistance (<jats:italic>mcr</jats:italic>) genes are plasmid-borne genes that confer resistance to colistin, an antibiotic used to treat severe bacterial infections. To date, eight known <jats:italic>mcr</jats:italic> homologues have been described (<jats:italic>mcr-1</jats:italic> to <jats:italic>-8</jats:italic>). Here, we describe <jats:italic>mcr-9</jats:italic>, a novel <jats:italic>mcr</jats:italic> homologue detected during routine <jats:italic>in silico</jats:italic> screening of sequenced <jats:italic>Salmonella</jats:italic> genomes for antimicrobial resistance genes. The amino acid sequence of <jats:italic>mcr-9</jats:italic>, detected in a multidrug-resistant (MDR) <jats:named-content content-type="genus-species">Salmonella enterica</jats:named-content> serotype Typhimurium (<jats:italic>S</jats:italic>. Typhimurium) strain isolated from a human patient in Washington State in 2010, most closely resembled <jats:italic>mcr-3</jats:italic>, aligning with 64.5% amino acid identity and 99.5% coverage using Translated Nucleotide BLAST (tblastn). The <jats:italic>S.</jats:italic> Typhimurium strain was tested for phenotypic resistance to colistin and was found to be sensitive at the 2-mg/liter European Committee on Antimicrobial Susceptibility Testing breakpoint under the tested conditions. <jats:italic>mcr-9</jats:italic> was cloned in colistin-susceptible <jats:named-content content-type="genus-species">Escherichia coli</jats:named-content> NEB5α under an IPTG (isopropyl-β-<jats:sc>d</jats:sc>-thiogalactopyranoside)-induced promoter to determine whether it was capable of conferring resistance to colistin when expressed in a heterologous host. Expression of <jats:italic>mcr-9</jats:italic> conferred resistance to colistin in <jats:named-content content-type="genus-species">E. coli</jats:named-content> NEB5α at 1, 2, and 2.5 mg/liter colistin, albeit at a lower level than <jats:italic>mcr-3</jats:italic>. Pairwise comparisons of the predicted protein structures associated with all nine <jats:italic>mcr</jats:italic> homologues (Mcr-1 to -9) revealed that Mcr-9, Mcr-3, Mcr-4, and Mcr-7 share a high degree of similarity at the structural level. Our results indicate that <jats:italic>mcr-9</jats:italic> is capable of conferring phenotypic resistance to colistin in <jats:named-content content-type="genus-species">Enterobacteriaceae</jats:named-content> and should be immediately considered when monitoring plasmid-mediated colistin resistance.
<jats:bold>IMPORTANCE</jats:bold> Colistin is a last-resort antibiotic that is used to treat severe infections caused by MDR and extensively drug-resistant (XDR) bacteria. The World Health Organization (WHO) has designated colistin as a “highest priority critically important antimicrobial for human medicine” (WHO, <jats:italic>Critically Important Antimicrobials for Human Medicine</jats:italic>, <jats:italic>5th revision</jats:italic>, 2017, <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="https://www.who.int/foodsafety/publications/antimicrobials-fifth/en/">https://www.who.int/foodsafety/publications/antimicrobials-fifth/en/</jats:ext-link>), as it is often one of the only therapies available for treating serious bacterial infections in critically ill patients. Plasmid-borne <jats:italic>mcr</jats:italic> genes that confer resistance to colistin pose a threat to public health at an international scale, as they can be transmitted via horizontal gene transfer and have the potential to spread globally. Therefore, the establishment of a complete reference of <jats:italic>mcr</jats:italic> genes that can be used to screen for plasmid-mediated colistin resistance is essential for developing effective control strategies.

Abstract

Mobilized colistin resistance (<jats:italic>mcr</jats:italic>) genes are plasmid-borne genes that confer resistance to colistin, an antibiotic used to treat severe bacterial infections. To date, eight known <jats:italic>mcr</jats:italic> homologues have been described (<jats:italic>mcr-1</jats:italic> to <jats:italic>-8</jats:italic>). Here, we describe <jats:italic>mcr-9</jats:italic>, a novel <jats:italic>mcr</jats:italic> homologue detected during routine <jats:italic>in silico</jats:italic> screening of sequenced <jats:italic>Salmonella</jats:italic> genomes for antimicrobial resistance genes. The amino acid sequence of <jats:italic>mcr-9</jats:italic>, detected in a multidrug-resistant (MDR) <jats:named-content content-type="genus-species">Salmonella enterica</jats:named-content> serotype Typhimurium (<jats:italic>S</jats:italic>. Typhimurium) strain isolated from a human patient in Washington State in 2010, most closely resembled <jats:italic>mcr-3</jats:italic>, aligning with 64.5% amino acid identity and 99.5% coverage using Translated Nucleotide BLAST (tblastn). The <jats:italic>S.</jats:italic> Typhimurium strain was tested for phenotypic resistance to colistin and was found to be sensitive at the 2-mg/liter European Committee on Antimicrobial Susceptibility Testing breakpoint under the tested conditions. <jats:italic>mcr-9</jats:italic> was cloned in colistin-susceptible <jats:named-content content-type="genus-species">Escherichia coli</jats:named-content> NEB5α under an IPTG (isopropyl-β-<jats:sc>d</jats:sc>-thiogalactopyranoside)-induced promoter to determine whether it was capable of conferring resistance to colistin when expressed in a heterologous host. Expression of <jats:italic>mcr-9</jats:italic> conferred resistance to colistin in <jats:named-content content-type="genus-species">E. coli</jats:named-content> NEB5α at 1, 2, and 2.5 mg/liter colistin, albeit at a lower level than <jats:italic>mcr-3</jats:italic>. Pairwise comparisons of the predicted protein structures associated with all nine <jats:italic>mcr</jats:italic> homologues (Mcr-1 to -9) revealed that Mcr-9, Mcr-3, Mcr-4, and Mcr-7 share a high degree of similarity at the structural level. Our results indicate that <jats:italic>mcr-9</jats:italic> is capable of conferring phenotypic resistance to colistin in <jats:named-content content-type="genus-species">Enterobacteriaceae</jats:named-content> and should be immediately considered when monitoring plasmid-mediated colistin resistance.
<jats:bold>IMPORTANCE</jats:bold> Colistin is a last-resort antibiotic that is used to treat severe infections caused by MDR and extensively drug-resistant (XDR) bacteria. The World Health Organization (WHO) has designated colistin as a “highest priority critically important antimicrobial for human medicine” (WHO, <jats:italic>Critically Important Antimicrobials for Human Medicine</jats:italic>, <jats:italic>5th revision</jats:italic>, 2017, <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="https://www.who.int/foodsafety/publications/antimicrobials-fifth/en/">https://www.who.int/foodsafety/publications/antimicrobials-fifth/en/</jats:ext-link>), as it is often one of the only therapies available for treating serious bacterial infections in critically ill patients. Plasmid-borne <jats:italic>mcr</jats:italic> genes that confer resistance to colistin pose a threat to public health at an international scale, as they can be transmitted via horizontal gene transfer and have the potential to spread globally. Therefore, the establishment of a complete reference of <jats:italic>mcr</jats:italic> genes that can be used to screen for plasmid-mediated colistin resistance is essential for developing effective control strategies.

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Item Type:Journal Article, refereed, original work
Communities & Collections:05 Vetsuisse Faculty > Institute of Food Safety and Hygiene
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Scopus Subject Areas:Life Sciences > Microbiology
Life Sciences > Virology
Uncontrolled Keywords:Salmonella enterica ; antibiotic resistance; colistin; mcr genes; mcr-9 ; mobilized colistin resistance; multidrug resistance; plasmid-mediated resistance
Language:English
Date:7 May 2019
Deposited On:14 Feb 2020 15:34
Last Modified:22 Apr 2020 23:08
Publisher:American Society for Microbiology
ISSN:2150-7511
OA Status:Gold
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1128/mbio.00853-19
PubMed ID:31064835

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