Defects in Efflux ( oprM ), β-Lactamase ( ampC ), and Lipopolysaccharide Transport ( lptE ) Genes Mediate Antibiotic Hypersusceptibility of Pseudomonas aeruginosa Strain Z61

Antibiotic hypersensitive bacterial mutants (e.g., ) are used to investigate intrinsic resistance and are exploited in antibacterial discovery to track weak antibacterial activity of novel inhibitor compounds. Z61 is one such drug-hypersusceptible strain generated by chemical mutagenesis, although t...

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Bibliographic Details
Published in:Antimicrobial agents and chemotherapy 2019-07, Vol.63 (7)
Main Authors: Shen, Xiaoyu, Johnson, Nicole V, Kreamer, Naomi N K, Barnes, S Whitney, Walker, John R, Woods, Angela L, Six, David A, Dean, C R
Format: Article
Language:English
Subjects:
Anti-Bacterial Agents
Anti-Bacterial Agents - pharmacology
Bacterial Outer Membrane Proteins - genetics
Bacterial Proteins
Bacterial Proteins - genetics
beta-Lactamases
beta-Lactamases - genetics
beta-Lactams - pharmacology
Biological Transport - genetics
Cell Membrane Permeability - genetics
Lipopolysaccharides
Lipopolysaccharides - metabolism
Mechanisms of Resistance
Membrane Transport Proteins
Membrane Transport Proteins - genetics
Microbial Sensitivity Tests - methods
Mutation - genetics
Pseudomonas aeruginosa
Pseudomonas aeruginosa - drug effects
Pseudomonas aeruginosa - genetics
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Summary:Antibiotic hypersensitive bacterial mutants (e.g., ) are used to investigate intrinsic resistance and are exploited in antibacterial discovery to track weak antibacterial activity of novel inhibitor compounds. Z61 is one such drug-hypersusceptible strain generated by chemical mutagenesis, although the genetic basis for hypersusceptibility is not fully understood. Genome sequencing of Z61 revealed nonsynonymous single-nucleotide polymorphisms in 153 genes relative to its parent strain, and three candidate mutations (in , , and ) predicted to mediate hypersusceptibility were characterized. The contribution of these mutations was confirmed by genomic restoration of the wild-type sequences, individually or in combination, in the Z61 background. Introduction of the mutation or genetic inactivation of and genes alone or together in the parent strain recapitulated drug sensitivities. This showed that disruption of (which encodes a major outer membrane efflux pump channel) increased susceptibility to pump substrate antibiotics, that inactivation of the inducible β-lactamase gene contributed to β-lactam susceptibility, and that mutation of the lipopolysaccharide transporter gene strongly altered the outer membrane permeability barrier, causing susceptibility to large antibiotics such as rifampin and also to β-lactams.
ISSN:0066-4804
1098-6596
DOI:10.1128/AAC.00784-19