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Antimicrob Agents Chemother. 2019 Dec 20;64(1). pii: e01490-19. doi: 10.1128/AAC.01490-19. Print 2019 Dec 20.

Mutations Reducing In Vitro Susceptibility to Novel LpxC Inhibitors in Pseudomonas aeruginosa and Interplay of Efflux and Nonefflux Mechanisms.

Author information

1
Infectious Diseases, Novartis Institutes for Biomedical Research, Emeryville, California, USA.
2
Chemical Biology and Therapeutics, Novartis Institutes for Biomedical Research, Emeryville, California, USA.
3
Genomics Institute of the Novartis Research Foundation, San Diego, California, USA.
4
Global Discovery Chemistry, Novartis Institutes for Biomedical Research, Emeryville, California, USA.
5
Infectious Diseases, Novartis Institutes for Biomedical Research, Emeryville, California, USA deancr10@yahoo.com.

Abstract

Upregulated expression of efflux pumps, lpxC target mutations, LpxC protein overexpression, and mutations in fabG were previously shown to mediate single-step resistance to the LpxC inhibitor CHIR-090 in P. aeruginosa Single-step selection experiments using three recently described LpxC inhibitors (compounds 2, 3, and 4) and mutant characterization showed that these mechanisms affect susceptibility to additional novel LpxC inhibitors. Serial passaging of P. aeruginosa wild-type and efflux pump-defective strains using the LpxC inhibitor CHIR-090 or compound 1 generated substantial shifts in susceptibility and underscored the interplay of efflux and nonefflux mechanisms. Whole-genome sequencing of CHIR-090 passage mutants identified efflux pump overexpression, fabG mutations, and novel mutations in fabF1 and in PA4465 as determinants of reduced susceptibility. Two new lpxC mutations, encoding A214V and G208S, that reduce susceptibility to certain LpxC inhibitors were identified in these studies, and we show that these and other target mutations differentially affect different LpxC inhibitor scaffolds. Lastly, the combination of target alteration (LpxCA214V) and upregulated expression of LpxC was shown to be tolerated in P. aeruginosa and could mediate significant decreases in susceptibility.

KEYWORDS:

LpxC inhibitor; Pseudomonas aeruginosa ; cumulative resistance; decreased susceptibility; efflux; target mutation

PMID:
31658970
DOI:
10.1128/AAC.01490-19

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