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

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dc.citation.issue5
dc.citation.volume6
dc.contributor.authorOlivera C
dc.contributor.authorCox MP
dc.contributor.authorRowlands GJ
dc.contributor.authorRakonjac J
dc.date.available2021
dc.date.issued2021-10-27
dc.description.abstractEffective 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 induces the SOS response consistent with its DNA-damaging effects, but we demonstrate that using FZ in combination with the other two compounds enables 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. IMPORTANCE Synergistic antibiotic combinations are a promising alternative strategy for developing effective therapies for multidrug-resistant bacterial infections. The synergistic combination of the existing antibiotics nitrofurans and vancomycin with 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.
dc.description.publication-statusPublished
dc.identifierhttp://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000712323600009&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=c5bb3b2499afac691c2e3c1a83ef6fef
dc.identifierARTN e00627-21
dc.identifier.citationMSPHERE, 2021, 6 (5)
dc.identifier.doi10.1128/mSphere.00627-21
dc.identifier.eissn2379-5042
dc.identifier.elements-id448456
dc.identifier.harvestedMassey_Dark
dc.relation.isPartOfMSPHERE
dc.relation.urihttps://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC8550143&blobtype=pdf
dc.rights(c) The Author/s 2021
dc.rightsCC BY 4.0
dc.subjectEnterobacteriaceae
dc.subjectEscherichia coli
dc.subjectGram-negative bacteria
dc.subjectantibiotic resistance
dc.subjectantibiotic synergy
dc.subjectbile salts
dc.subjectfurazolidone
dc.subjectnitrofuran
dc.subjectsodium deoxycholate
dc.subjectvancomycin
dc.titleCorrelated Transcriptional Responses Provide Insights into the Synergy Mechanisms of the Furazolidone, Vancomycin, and Sodium Deoxycholate Triple Combination in Escherichia coli.
dc.typeJournal article
pubs.notesNot known
pubs.organisational-group/Massey University
pubs.organisational-group/Massey University/College of Sciences
pubs.organisational-group/Massey University/College of Sciences/School of Natural Sciences
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