OmpK36-mediated Carbapenem resistance attenuates ST258 Klebsiella pneumoniae in vivo

Joshua L. C. Wong, Maria Romano, Louise E. Kerry, Hok-Sau Kwong, Wen-Wen Low, Stephen J. Brett, Abigail Clements, Konstantinos Beis and Gad Frankel ()
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Joshua L. C. Wong: Imperial College London
Maria Romano: Imperial College London
Louise E. Kerry: Imperial College London
Hok-Sau Kwong: Imperial College London
Wen-Wen Low: Imperial College London
Stephen J. Brett: Imperial College London
Abigail Clements: Imperial College London
Konstantinos Beis: Imperial College London
Gad Frankel: Imperial College London

Nature Communications, 2019, vol. 10, issue 1, 1-10

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11756-y

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