Correlated transcriptional responses provide insights into the synergy mechanisms of the furazolidone, vancomycin and sodium deoxycholate triple combination in Escherichia coli

Olivera, C.; Cox, M. P.; Rowlands, G. J.; Rakonjac, J.

doi:10.1101/2021.07.13.452286

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bioRxiv · 10.1101/2021.07.13.452286

Correlated transcriptional responses provide insights into the synergy mechanisms of the furazolidone, vancomycin and sodium deoxycholate triple combination in Escherichia coli

Olivera, C.·Cox, M. P.·Rowlands, G. J.·Rakonjac, J.

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Abstract

Effective therapeutic options are urgently needed to tackle antibiotic resistance. Furazolidone (FZ), vancomycin (VAN), and sodium deoxycholate (DOC) show promise as their combination can synergistically inhibit the growth of, and kill, multidrug-resistant Gram-negative bacteria that are classified as critical priority by the World Health Organization. Here, we investigated the mechanisms of action and synergy of this drug combination using a transcriptomics approach in the model bacterium Escherichia coli. We show that FZ and DOC elicit highly similar gene perturbations indicative of iron starvation, decreased respiration and metabolism, and translational stress. In contrast, VAN induced envelope stress responses, in agreement with its known role in peptidoglycan synthesis inhibition. FZ induced the SOS response consistent with its DNA damaging effects, but we demonstrate that using FZ in combination with the other two compounds enables use of lower dosages and largely mitigates its mutagenic effects. Based on the gene expression changes identified, we propose a synergy mechanism where the combined effects of FZ, VAN, and DOC amplify damage to Gram-negative bacteria while simultaneously suppressing antibiotic resistance mechanisms. ImportanceSynergistic combinations of existing antibacterials against multidrug-resistant "superbugs" are an alternative strategy to costly and arduous development of novel antibacterial molecules. The synergistic combination of nitrofurans, vancomycin and sodium deoxycholate shows promise in inhibiting and killing multidrug-resistant Gram-negative bacteria. We examined the mechanism of action and synergy of these three antibacterials, and proposed a mechanistic basis for their synergy. Our results highlight much needed mechanistic information necessary to advance this combination as a potential therapy.

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Olivera, C., Cox, M. P., Rowlands, G. J., Rakonjac, J.. 2021-07-14. Correlated transcriptional responses provide insights into the synergy mechanisms of the furazolidone, vancomycin and sodium deoxycholate triple combination in Escherichia coli. https://doi.org/10.1101/2021.07.13.452286

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