Oxidative stress antagonizes fluoroquinolone drug sensitivity via the SoxR-SUF Fe-S cluster homeostatic axis

Audrey Gerstel; Jordi Zamarreño Beas; Yohann Duverger; Emmanuelle Bouveret; Frédéric Barras; Béatrice Py

doi:10.1371/journal.pgen.1009198

Oxidative stress antagonizes fluoroquinolone drug sensitivity via the SoxR-SUF Fe-S cluster homeostatic axis

PLoS Genet. 2020 Nov 2;16(11):e1009198. doi: 10.1371/journal.pgen.1009198. eCollection 2020 Nov.

Authors

Audrey Gerstel¹, Jordi Zamarreño Beas¹, Yohann Duverger¹, Emmanuelle Bouveret², Frédéric Barras^{1

2}, Béatrice Py¹

Affiliations

¹ Laboratoire de Chimie Bactérienne, Aix-Marseille Université-CNRS UMR7283, Institut de Microbiologie de la Méditerranée, Marseille, France.
² SAMe Unit, Département de Microbiologie, Institut Pasteur, CNRS UMR IMM 2001, Paris, France.

Abstract

The level of antibiotic resistance exhibited by bacteria can vary as a function of environmental conditions. Here, we report that phenazine-methosulfate (PMS), a redox-cycling compound (RCC) enhances resistance to fluoroquinolone (FQ) norfloxacin. Genetic analysis showed that E. coli adapts to PMS stress by making Fe-S clusters with the SUF machinery instead of the ISC one. Based upon phenotypic analysis of soxR, acrA, and micF mutants, we showed that PMS antagonizes fluoroquinolone toxicity by SoxR-mediated up-regulation of the AcrAB drug efflux pump. Subsequently, we showed that despite the fact that SoxR could receive its cluster from either ISC or SUF, only SUF is able to sustain efficient SoxR maturation under exposure to prolonged PMS period or high PMS concentrations. This study furthers the idea that Fe-S cluster homeostasis acts as a sensor of environmental conditions, and because its broad influence on cell metabolism, modifies the antibiotic resistance profile of E. coli.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-Bacterial Agents / pharmacology*
Anti-Bacterial Agents / therapeutic use
Bacterial Proteins / metabolism*
Carrier Proteins / genetics
Carrier Proteins / metabolism
Drug Antagonism
Drug Resistance, Bacterial / drug effects
Drug Resistance, Bacterial / genetics*
Escherichia coli / drug effects
Escherichia coli / physiology*
Escherichia coli Infections / drug therapy
Escherichia coli Infections / microbiology
Escherichia coli Proteins / genetics
Escherichia coli Proteins / metabolism
Gene Expression Regulation, Bacterial
Humans
Iron-Sulfur Proteins / metabolism*
Methylphenazonium Methosulfate / pharmacology
Microbial Sensitivity Tests
Norfloxacin / pharmacology
Oxidative Stress / drug effects
Oxidative Stress / genetics
Transcription Factors / metabolism*

Substances

AcrAB-TolC protein, E coli
Anti-Bacterial Agents
Bacterial Proteins
Carrier Proteins
Escherichia coli Proteins
Iron-Sulfur Proteins
Transcription Factors
SoxR protein, Bacteria
Methylphenazonium Methosulfate
Norfloxacin

Grants and funding

This work was supported by grants from the CNRS, the JPIAMR “Combinatorial” grant, Aix‐Marseille Université, Institut Pasteur and the ANR-10-LABX-62-IBEID. A.G. and J.Z. were supported by fellowships from Ministère de l’Enseignement et de la Recherche. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.