OmpK36-mediated Carbapenem resistance attenuates ST258 Klebsiella pneumoniae in vivo

Nat Commun. 2019 Sep 2;10(1):3957. doi: 10.1038/s41467-019-11756-y.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / genetics*
  • Bacterial Proteins / metabolism
  • Carbapenems / pharmacology*
  • Crystallography, X-Ray
  • Drug Resistance, Bacterial / genetics*
  • Female
  • Klebsiella Infections / drug therapy*
  • Klebsiella Infections / microbiology
  • Klebsiella pneumoniae / genetics*
  • Klebsiella pneumoniae / pathogenicity
  • Mice, Inbred BALB C
  • Microbial Sensitivity Tests
  • Mutation
  • Porins / chemistry
  • Porins / genetics*
  • Porins / metabolism
  • Sequence Homology, Amino Acid
  • Virulence / genetics


  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Carbapenems
  • OmpK36 protein, Klebsiella pneumoniae
  • Porins