6rcp

Publication Abstract from PubMed

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.

OmpK36-mediated Carbapenem resistance attenuates ST258 Klebsiella pneumoniae in vivo.,Wong JLC, Romano M, Kerry LE, Kwong HS, Low WW, Brett SJ, Clements A, Beis K, Frankel G Nat Commun. 2019 Sep 2;10(1):3957. doi: 10.1038/s41467-019-11756-y. PMID:31477712^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.