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- Title
OmpK36-mediated Carbapenem resistance attenuates ST258 Klebsiella pneumoniae in vivo.
- Authors
Wong, Joshua L. C.; Romano, Maria; Kerry, Louise E.; Kwong, Hok-Sau; Low, Wen-Wen; Brett, Stephen J.; Clements, Abigail; Beis, Konstantinos; Frankel, Gad
- 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. Carbapenem-resistance in Klebsiella pneumoniae sequence type ST258 can be enhanced by modification of the porins OmpK35 and OmpK36. Here, Wong et al. solve the crystal structure of a clinical ST258 OmpK36 variant, elucidating the mechanism of resistance and consequences on pathogenicity in vivo.
- Subjects
KLEBSIELLA pneumoniae; KLEBSIELLA infections; VENTILATOR-associated pneumonia; CARBAPENEMS; BACTERIAL growth; CRYSTAL structure; DNA insertion elements; RESISTANCE to change
- Publication
Nature Communications, 2019, Vol 10, Issue 1, pN.PAG
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-019-11756-y