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Impact of inducible blaDHA-1 on susceptibility of Klebsiella pneumoniae clinical isolates to LYS228 and identification of chromosomal mpl mutations mediating upregulation of plasmid borne DHA-1 expression

Jones, Adriana and Ranjitkar, Srijan and Lopez, Sara and Li, Cindy and Blais, Johanne and Reck, Folkert and Dean, Charles (2018) Impact of inducible blaDHA-1 on susceptibility of Klebsiella pneumoniae clinical isolates to LYS228 and identification of chromosomal mpl mutations mediating upregulation of plasmid borne DHA-1 expression. Antimicrobial agents and chemotherapy, 62 (10).

Abstract

A panel of twenty three K. pneumoniae clinical isolates harboring plasmid-borne inducible β-lactamase DHA-1 (blaDHA-1) exhibited a wide range of susceptibilities to the novel monobactam LYS228 (MIC range 0.125 - >64 µg/mL). This panel was considerably less susceptible (MIC ≥ 8 µg/mL for 9/23 of the isolates) than was a previously reported Enterobacteriaceae strain panel comprised of 88 isolates expressing ESBLs, KPCs and MBL (MIC90 of 2 µg/mL), suggesting that blaDHA-1 can impact LYS228 susceptibility in clinical isolates. Mutants with decreased in vitro susceptibility to LYS228 and upregulated expression of blaDHA-1 were selected in vitro from K. pneumoniae blaDHA-1 strains. These had mutations in the chromosomal peptidoglycan recycling gene mpl. Pre-existing mpl mutations were identified among our clinical strains and these had strongly upregulated expression of blaDHA-1 and reduced susceptibility to LYS228. Therefore we have identified a novel mechanism of blaDHA upregulation in K. pneumoniae clinical isolates, furthering our understanding of the factors underlying β-lactam resistance and the variability in β-lactam susceptibility among these clinical strains.

Item Type: Article
Date Deposited: 28 Aug 2018 00:45
Last Modified: 28 Aug 2018 00:45
URI: https://oak.novartis.com/id/eprint/36551

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