Correlated Transcriptional Responses Provide Insights into the Synergy Mechanisms of the Furazolidone, Vancomycin, and Sodium Deoxycholate Triple Combination in Escherichia coli

Olivera, Catrina; Cox, Murray P.; Rowlands, Gareth J.; Rakonjac, Jasna

doi:10.1128/msphere.00627-21

Cited by 1 publication

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References 72 publications

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“…We have previously shown furazolidone-vancomycin synergy against Gram-negative bacteria (5) and studied the bacterial response to this combination using transcriptomics (RNAseq) (14). In this work, we sought to further understand the synergy and potential resistance mechanisms to this combination by selecting and characterizing E. coli mutants isolated on furazolidone-vancomycin plates.…”

Section: Resistance To the Furazolidone-vancomycin Combinationmentioning

confidence: 99%

Mutations in the riboflavin biosynthesis pathway confer resistance to furazolidone and abolish the synergistic interaction between furazolidone and vancomycin inEscherichia coli

Wykes,

Le,

Rakonjac

2024

Preprint

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Antibiotic combinations are a promising strategy to counteract the global problem of increasing antibiotic resistance. We have previously demonstrated furazolidone-vancomycin synergy against Gram-negative pathogens. Here, we selectedEscherichia coliprogeny for growth on the furazolidone-vancomycin combination to which the parent was sensitive. We show that selected clones were associated with increased resistance to neither, only one of, or both furazolidone and vancomycin, but in all cases were associated with a decrease in furazolidone-vancomycin synergy. Among a variety of gene mutations identified in this screen, we investigated the mechanism behind the most frequently arising mutations, those in the riboflavin biosynthesis genesribBandribE, and found them to act predominantly through decreasing the activity of the NfsA and NfsB nitroreductases, which have FMN (flavin mononucleotide) or FAD (flavin adenine dinucleotide) as a prosthetic group. We further show that theribB/ribEmutants isolated in our screen are riboflavin semi-auxotrophs. Riboflavin supplementation restored the normal growth of theribB/ribEmutants but not the furazolidone sensitivity.

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Section: Resistance To the Furazolidone-vancomycin Combinationmentioning

confidence: 99%