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OmpK36-mediated Carbapenem resistance attenuates ST258 Klebsiella pneumoniae in vivo

Author

Listed:
  • Joshua L. C. Wong

    (Imperial College London
    Imperial College London
    Imperial College London)

  • Maria Romano

    (Imperial College London
    Research Complex at Harwell)

  • Louise E. Kerry

    (Imperial College London
    Imperial College London)

  • Hok-Sau Kwong

    (Imperial College London
    Research Complex at Harwell)

  • Wen-Wen Low

    (Imperial College London
    Imperial College London)

  • Stephen J. Brett

    (Imperial College London)

  • Abigail Clements

    (Imperial College London
    Imperial College London)

  • Konstantinos Beis

    (Imperial College London
    Research Complex at Harwell)

  • Gad Frankel

    (Imperial College London
    Imperial College London)

Abstract

Carbapenem-resistance in Klebsiella pneumoniae (KP) sequence type ST258 is mediated by carbapenemases (e.g. KPC-2) and loss or modification of the major non-selective porins OmpK35 and OmpK36. However, the mechanism underpinning OmpK36-mediated resistance and consequences of these changes on pathogenicity remain unknown. By solving the crystal structure of a clinical ST258 OmpK36 variant we provide direct structural evidence of pore constriction, mediated by a di-amino acid (Gly115-Asp116) insertion into loop 3, restricting diffusion of both nutrients (e.g. lactose) and Carbapenems. In the presence of KPC-2 this results in a 16-fold increase in MIC to Meropenem. Additionally, the Gly-Asp insertion impairs bacterial growth in lactose-containing medium and confers a significant in vivo fitness cost in a murine model of ventilator-associated pneumonia. Our data suggests that the continuous selective pressure imposed by widespread Carbapenem utilisation in hospital settings drives the expansion of KP expressing Gly-Asp insertion mutants, despite an associated fitness cost.

Suggested Citation

  • Joshua L. C. Wong & Maria Romano & Louise E. Kerry & Hok-Sau Kwong & Wen-Wen Low & Stephen J. Brett & Abigail Clements & Konstantinos Beis & Gad Frankel, 2019. "OmpK36-mediated Carbapenem resistance attenuates ST258 Klebsiella pneumoniae in vivo," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11756-y
    DOI: 10.1038/s41467-019-11756-y
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