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Resolving colistin resistance and heteroresistance in Enterobacter species

Author

Listed:
  • Swapnil Prakash Doijad

    (German Center for Infection Research (DZIF)
    Justus Liebig University)

  • Nicolas Gisch

    (Priority Area Infections, Research Center Borstel, Leibniz Lung Center)

  • Renate Frantz

    (German Center for Infection Research (DZIF)
    Justus Liebig University)

  • Bajarang Vasant Kumbhar

    (NMIMS (Deemed-to-be) University)

  • Jane Falgenhauer

    (German Center for Infection Research (DZIF)
    Justus Liebig University)

  • Can Imirzalioglu

    (German Center for Infection Research (DZIF)
    Justus Liebig University)

  • Linda Falgenhauer

    (German Center for Infection Research (DZIF)
    Justus Liebig University
    Justus Liebig University)

  • Alexander Mischnik

    (German Center for Infection Research (DZIF)
    University of Lübeck)

  • Jan Rupp

    (German Center for Infection Research (DZIF)
    University of Lübeck)

  • Michael Behnke

    (German Center for Infection Research (DZIF)
    Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität of Berlin and Berlin Institute of Health, Institute of Hygiene and Environmental Medicine)

  • Michael Buhl

    (German Center for Infection Research (DZIF)
    Tübingen University
    Tübingen University
    Paracelsus Medical University, Klinikum Nürnberg)

  • Simone Eisenbeis

    (German Center for Infection Research (DZIF)
    Tübingen University)

  • Petra Gastmeier

    (German Center for Infection Research (DZIF)
    Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität of Berlin and Berlin Institute of Health, Institute of Hygiene and Environmental Medicine)

  • Hanna Gölz

    (German Center for Infection Research (DZIF)
    Albert-Ludwigs-University)

  • Georg Alexander Häcker

    (German Center for Infection Research (DZIF)
    Albert-Ludwigs-University)

  • Nadja Käding

    (German Center for Infection Research (DZIF)
    University of Lübeck)

  • Winfried V. Kern

    (German Center for Infection Research (DZIF)
    Faculty of Medicine and University Hospital and Medical Center, Albert-Ludwigs-University)

  • Axel Kola

    (German Center for Infection Research (DZIF)
    Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität of Berlin and Berlin Institute of Health, Institute of Hygiene and Environmental Medicine)

  • Evelyn Kramme

    (University of Lübeck
    Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität of Berlin and Berlin Institute of Health, Institute of Hygiene and Environmental Medicine)

  • Silke Peter

    (German Center for Infection Research (DZIF)
    Tübingen University)

  • Anna M. Rohde

    (German Center for Infection Research (DZIF)
    Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität of Berlin and Berlin Institute of Health, Institute of Hygiene and Environmental Medicine)

  • Harald Seifert

    (German Center for Infection Research (DZIF)
    Faculty of Medicine and University Hospital Cologne, University of Cologne)

  • Evelina Tacconelli

    (German Center for Infection Research (DZIF)
    Tübingen University)

  • Maria J. G. T. Vehreschild

    (German Center for Infection Research (DZIF)
    Faculty of Medicine and University Hospital Cologne, University of Cologne
    University Hospital Frankfurt, Goethe University Frankfurt)

  • Sarah V. Walker

    (German Center for Infection Research (DZIF)
    Faculty of Medicine and University Hospital Cologne, University of Cologne)

  • Janine Zweigner

    (German Center for Infection Research (DZIF)
    Faculty of Medicine and University Hospital Cologne, University of Cologne)

  • Dominik Schwudke

    (German Center for Infection Research (DZIF)
    Priority Area Infections, Research Center Borstel, Leibniz Lung Center
    Member of the German Center for Lung Research (DZL), Site: Research Center Borstel)

  • Trinad Chakraborty

    (German Center for Infection Research (DZIF)
    Justus Liebig University)

Abstract

Species within the Enterobacter cloacae complex (ECC) include globally important nosocomial pathogens. A three-year study of ECC in Germany identified Enterobacter xiangfangensis as the most common species (65.5%) detected, a result replicated by examining a global pool of 3246 isolates. Antibiotic resistance profiling revealed widespread resistance and heteroresistance to the antibiotic colistin and detected the mobile colistin resistance (mcr)−9 gene in 19.2% of all isolates. We show that resistance and heteroresistance properties depend on the chromosomal arnBCADTEF gene cassette whose products catalyze transfer of L-Ara4N to lipid A. Using comparative genomics, mutational analysis, and quantitative lipid A profiling we demonstrate that intrinsic lipid A modification levels are genospecies-dependent and governed by allelic variations in phoPQ and mgrB, that encode a two-component sensor-activator system and specific inhibitor peptide. By generating phoPQ chimeras and combining them with mgrB alleles, we show that interactions at the pH-sensing interface of the sensory histidine kinase phoQ dictate arnBCADTEF expression levels. To minimize therapeutic failures, we developed an assay that accurately detects colistin resistance levels for any ECC isolate.

Suggested Citation

  • Swapnil Prakash Doijad & Nicolas Gisch & Renate Frantz & Bajarang Vasant Kumbhar & Jane Falgenhauer & Can Imirzalioglu & Linda Falgenhauer & Alexander Mischnik & Jan Rupp & Michael Behnke & Michael Bu, 2023. "Resolving colistin resistance and heteroresistance in Enterobacter species," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-022-35717-0
    DOI: 10.1038/s41467-022-35717-0
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    References listed on IDEAS

    as
    1. Ruobing Wang & Lucy Dorp & Liam P. Shaw & Phelim Bradley & Qi Wang & Xiaojuan Wang & Longyang Jin & Qing Zhang & Yuqing Liu & Adrien Rieux & Thamarai Dorai-Schneiders & Lucy Anne Weinert & Zamin Iqbal, 2018. "The global distribution and spread of the mobilized colistin resistance gene mcr-1," Nature Communications, Nature, vol. 9(1), pages 1-9, December.
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    Cited by:

    1. E. A. R. Portal & K. Sands & C. Farley & I. Boostrom & E. Jones & M. Barrell & M. J. Carvalho & R. Milton & K. Iregbu & F. Modibbo & S. Uwaezuoke & C. Akpulu & L. Audu & C. Edwin & A. H. Yusuf & A. Ad, 2024. "Characterisation of colistin resistance in Gram-negative microbiota of pregnant women and neonates in Nigeria," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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