Parole chiave: Outer Membrane Protein, Klebsiella Pneumoniae, Carbapenem-Resistance
Centre for Molecular Bacteriology and Infection, Imperial College London, London, UK Department of Life Sciences, Imperial College London, London, UK Rutherford Appleton Laboratory, Research Complex at Harwell, Didcot, Oxfordshire, UK
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.
10 Records (10 escludendo Abstract e Conferenze). Impact factor totale: 31.328 (31.328 escludendo Abstract e Conferenze). Impact factor a 5 anni totale: 35.316 (35.316 escludendo Abstract e Conferenze).