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

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

doi:10.1371/journal.pgen.1009198

Cited by 15 publications

(23 citation statements)

References 60 publications

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“…This is a significant step forward as anaerobiosis is well known to reduce antibacterial activity of AG. This study extands our previous work [4,30,31]…”

Section: Discussionsupporting

confidence: 58%

The AAA+ ATPase RavA-ViaA complex sensitizes Escherichia coli to aminoglycosides under anaerobic low energy conservation conditions

Khoury

Beas

Huguenot

et al. 2022

Preprint

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Aminoglycosides have been used against Gram-negative bacteria for decades. Yet, uncertainties remain about various aspects of their uptake mechanism. Moreover their killing efficiency is well known to vary as a function of growth conditions and types of metabolism used by the targeted bacterium. Here we show that RavA, an AAA+ ATPase from the MoxR subfamily, associated with its VWA-containing partner, ViaA sensitize E. coli to lethal concentrations of AG, including gentamycin (Gm) and tobramycin, but not of antibiotics of other classes. We show this sensitizing effect to be due to enhanced Gm uptake in a proton motive force dependent manner. We evaluated the influence of RavA ViaA throughout a series of growth conditions, including aerobiosis and anaerobiosis. This led us to observe that the sensitizing effect of RavA ViaA varies with the respiratory chain used, i.e. RavA ViaA influence was prominent in the absence of exogenous electron acceptor or with fumarate, i.e. in poor energy conservation conditions, and dispensable in the presence of nitrate or oxygen, i.e. in high level of energy conservation. We propose RavA ViaA to be able to sense energetic state of the cell and to be used under low energy conditions for facilitating uptake of chemicals across the membrane, including Gm.

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“…This is a significant step forward as anaerobiosis is well known to reduce antibacterial activity of AG. This study extands our previous work [4,30,31]…”

Section: Discussionsupporting

confidence: 58%

The AAA+ ATPase RavA-ViaA complex sensitizes Escherichia coli to aminoglycosides under anaerobic low energy conservation conditions

Khoury

Beas

Huguenot

et al. 2022

Preprint

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“…[41][42][43][44][45][46][47] Note however that Atype are also instrumental in maturation of [2Fe-2S] containing proteins such as IscR or SoxR in E. coli. 48,49 The observation of a [2Fe-2S] cluster on as-purified SufBC2D is in agreement with this view. The proposed [3Fe-3S] cluster is reproducibly obtained and therefore is unlikely an artifact.…”

Section: Models For Fe-s Clusters On Sufbc2dsupporting

confidence: 81%

A multidisciplinary analysis of the as-isolated Escherichia coli SufBC₂D complex reveals the presence of two new iron-sulfur clusters

Veronesi¹,

Pérard²,

Clémancey³

et al. 2022

Preprint

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Iron-sulfur (Fe-S) clusters are essential inorganic cofactors dedicated to a wide range of biological functions including electron transfer and catalysis. Specialized multi-protein machineries present in all types of organisms support their biosynthesis. These machineries encompass a scaffold protein on which Fe-S clusters are assembled before being transferred to cellular targets. Here, we describe the first characterization of the native Fe-S cluster of the anaerobically purified SufBC2D scaffold from Escherichia coli by XAS, Mossbauer, UV-visible absorption and EPR spectroscopy. Interestingly, we propose that SufBC2D harbors two types of Fe-S cluster, a [2Fe-2S] cluster with an unprecedented usual coordination and a previously unreported [3Fe-3S] cluster. These data combined with mutagenesis and biochemistry allow to propose ligands for these clusters. These results support the hypothesis that both SufB and SufD are involved in Fe-S cluster ligation and are discussed in the context of Fe-S cluster biogenesis where both [2Fe-2S] and [4Fe-4S] clusters need to mature cellular Fe-S protein targets

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“…Recent work indicates that PYO and other phenazines may affect such tests (Gerstel et al, 2020;Zhu et al, 2019). However, current AST methods are blind to potential modulating effects of redoxactive secondary metabolites.…”

Section: Assessing the Effects Of Redox-active Secondary Metabolites ...mentioning

confidence: 99%

Phenazines and toxoflavin act as interspecies modulators of resilience to diverse antibiotics

Meirelles

Newman

2022

Molecular Microbiology

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Bacterial opportunistic pathogens make diverse secondary metabolites both in the natural environment and when causing infections, yet how these molecules mediate microbial interactions and their consequences for antibiotic treatment are still poorly understood. Here, we explore the role of three redox‐active secondary metabolites, pyocyanin, phenazine‐1‐carboxylic acid, and toxoflavin, as interspecies modulators of antibiotic resilience. We find that these molecules dramatically change susceptibility levels of diverse bacteria to clinical antibiotics. Pyocyanin and phenazine‐1‐carboxylic acid are made by Pseudomonas aeruginosa, while toxoflavin is made by Burkholderia gladioli, organisms that infect cystic fibrosis and other immunocompromised patients. All molecules alter the susceptibility profile of pathogenic species within the “Burkholderia cepacia complex” to different antibiotics, either antagonizing or potentiating their effects, depending on the drug’s class. Defense responses regulated by the redox‐sensitive transcription factor SoxR potentiate the antagonistic effects these metabolites have against fluoroquinolones, and the presence of genes encoding SoxR and the efflux systems it regulates can be used to predict how these metabolites will affect antibiotic susceptibility of different bacteria. Finally, we demonstrate that inclusion of secondary metabolites in standard protocols used to assess antibiotic resistance can dramatically alter the results, motivating the development of new tests for more accurate clinical assessment.

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

Cited by 15 publications

References 60 publications

The AAA+ ATPase RavA-ViaA complex sensitizes Escherichia coli to aminoglycosides under anaerobic low energy conservation conditions

The AAA+ ATPase RavA-ViaA complex sensitizes Escherichia coli to aminoglycosides under anaerobic low energy conservation conditions

A multidisciplinary analysis of the as-isolated Escherichia coli SufBC₂D complex reveals the presence of two new iron-sulfur clusters

Phenazines and toxoflavin act as interspecies modulators of resilience to diverse antibiotics

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

Cited by 15 publications

References 60 publications

The AAA+ ATPase RavA-ViaA complex sensitizes Escherichia coli to aminoglycosides under anaerobic low energy conservation conditions

The AAA+ ATPase RavA-ViaA complex sensitizes Escherichia coli to aminoglycosides under anaerobic low energy conservation conditions

A multidisciplinary analysis of the as-isolated Escherichia coli SufBC2D complex reveals the presence of two new iron-sulfur clusters

Phenazines and toxoflavin act as interspecies modulators of resilience to diverse antibiotics

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A multidisciplinary analysis of the as-isolated Escherichia coli SufBC₂D complex reveals the presence of two new iron-sulfur clusters