Widespread emergence of OmpK36 loop 3 insertions among multidrug-resistant clones of Klebsiella pneumoniae.

Title: Widespread emergence of OmpK36 loop 3 insertions among multidrug-resistant clones of Klebsiella pneumoniae.
Authors: David, S
Wong, JLC
Sanchez-Garrido, J
Kwong, H-S
Low, WW
Morecchiato, F
Giani, T
Rossolini, GM
Brett, SJ
Clements, A
Beis, K
Aanensen, DM
Frankel, G
Item Type: Journal Article
Abstract: Mutations in outer membrane porins act in synergy with carbapenemase enzymes to increase carbapenem resistance in the important nosocomial pathogen, Klebsiella pneumoniae (KP). A key example is a di-amino acid insertion, Glycine-Aspartate (GD), in the extracellular loop 3 (L3) region of OmpK36 which constricts the pore and restricts entry of carbapenems into the bacterial cell. Here we combined genomic and experimental approaches to characterise the diversity, spread and impact of different L3 insertion types in OmpK36. We identified L3 insertions in 3588 (24.1%) of 14,888 KP genomes with an intact ompK36 gene from a global collection. GD insertions were most common, with a high concentration in the ST258/512 clone that has spread widely in Europe and the Americas. Aspartate (D) and Threonine-Aspartate (TD) insertions were prevalent in genomes from Asia, due in part to acquisitions by KP sequence types ST16 and ST231 and subsequent clonal expansions. By solving the crystal structures of novel OmpK36 variants, we found that the TD insertion causes a pore constriction of 41%, significantly greater than that achieved by GD (10%) or D (8%), resulting in the highest levels of resistance to selected antibiotics. We show that in the absence of antibiotics KP mutants harbouring these L3 insertions exhibit both an in vitro and in vivo competitive disadvantage relative to the isogenic parental strain expressing wild type OmpK36. We propose that this explains the reversion of GD and TD insertions observed at low frequency among KP genomes. Finally, we demonstrate that strains expressing L3 insertions remain susceptible to drugs targeting carbapenemase-producing KP, including novel beta lactam-beta lactamase inhibitor combinations. This study provides a contemporary global view of OmpK36-mediated resistance mechanisms in KP, integrating surveillance and experimental data to guide treatment and drug development strategies.
Issue Date: Jul-2022
Date of Acceptance: 15-Jun-2022
URI: http://hdl.handle.net/10044/1/98955
DOI: 10.1371/journal.ppat.1010334
ISSN: 1553-7366
Publisher: Public Library of Science (PLoS)
Start Page: 1
End Page: 23
Journal / Book Title: PLoS Pathogens
Volume: 18
Issue: 7
Copyright Statement: © 2022 David et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Sponsor/Funder: Wellcome Trust
Medical Research Council (MRC)
Funder's Grant Number: 107057/Z/15/Z
MR/N020103/1
Keywords: Anti-Bacterial Agents
Aspartic Acid
Bacterial Proteins
Clone Cells
Humans
Klebsiella Infections
Klebsiella pneumoniae
Microbial Sensitivity Tests
Porins
beta-Lactamases
Clone Cells
Humans
Klebsiella pneumoniae
Klebsiella Infections
beta-Lactamases
Aspartic Acid
Bacterial Proteins
Porins
Anti-Bacterial Agents
Microbial Sensitivity Tests
Anti-Bacterial Agents
Aspartic Acid
Bacterial Proteins
Clone Cells
Humans
Klebsiella Infections
Klebsiella pneumoniae
Microbial Sensitivity Tests
Porins
beta-Lactamases
Virology
0605 Microbiology
1107 Immunology
1108 Medical Microbiology
Publication Status: Published
Conference Place: United States
Online Publication Date: 2022-07-11
Appears in Collections:Department of Surgery and Cancer
Cell and Molecular Biology
Faculty of Natural Sciences



This item is licensed under a Creative Commons License Creative Commons