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OmpK36-mediated Carbapenem resistance attenuates ST258 Klebsiella pneumoniae in vivo

DOI: 10.1038/s41467-019-11756-y DOI Help

Authors: Joshua L. C. Wong (Imperial College London) , Maria Romano (Imperial College London; Research Complex at Harwell) , Louise E. Kerry (Imperial College London) , Hok-sau Kwong (Imperial College London; Research Complex at Harwell) , Wen-wen Low (Imperial College London) , Stephen J. Brett (Imperial College London) , Abigail Clements (Imperial College London) , Konstantinos Beis (Diamond Light Source) , Gad Frankel (Imperial College London)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 10

State: Published (Approved)
Published: September 2019
Diamond Proposal Number(s): 17221

Open Access Open Access

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.

Journal Keywords: Antimicrobials; Bacteria; Clinical microbiology; Policy and public health in microbiology

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Documents:
s41467-019-11756-y.pdf