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

Audrey Gerstel,Béatrice Py,Yohann Duverger,Emmanuelle Bouveret,Frédéric Barras,Jordi Zamarreño Beas,Melanie Blokesch

doi:10.1371/journal.pgen.1009198

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.

Highlights

Drug combination is a potent strategy against the worrying rise of multi-drug resistant bacteria as it reduces the chance of resistance acquisition [1,2]
Our study investigates how phenazine compounds, which are widely present in the environment, impact antibiotic resistance of the Gram-negative bacteria Escherichia coli
We show that the mechanism E. coli is using for synthesizing Fe-S clusters controls the phenazine/fluoroquinolone antagonism

Summary

Introduction

Drug combination is a potent strategy against the worrying rise of multi-drug resistant bacteria as it reduces the chance of resistance acquisition [1,2]. Drugs causing oxidative stress, such as paraquat or plumbagin, were found to antagonize antibiotics of different families including quinolones [5]. This was consistent with the previous observation that redox-cycling compounds (RCC) such as paraquat or plumbagin enhanced both survival and persister formation in the presence of the oxolinic acid fluoroquinolone [6,7]. E. coli possesses two such machineries, ISC and SUF, which synthesize and deliver Fe-S clusters to about 150 apo-proteins. ISC is the housekeeping machinery, employed during balanced growth conditions, and SUF is the stressresponding one [9,10,11,12,13,14]. SUF is inefficient at targeting clusters to the protonmotive force (pmf)-producing respiratory complexes, and a reduced aminoglycoside uptake ensues [8]

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Discussion

Conclusion