In vitro synergy between sodium deoxycholate and furazolidone against enterobacteria

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dc.citation.issue1
dc.citation.volume20
dc.contributor.authorLe VVH
dc.contributor.authorOlivera C
dc.contributor.authorSpagnuolo J
dc.contributor.authorDavies IG
dc.contributor.authorRakonjac J
dc.date.accessioned2024-01-08T00:41:31Z
dc.date.accessioned2024-07-25T06:35:15Z
dc.date.available2019-01-11
dc.date.available2024-01-08T00:41:31Z
dc.date.available2024-07-25T06:35:15Z
dc.date.issued2020-01-06
dc.description.abstractBackground Antimicrobial combinations have been proven as a promising approach in the confrontation with multi-drug resistant bacterial pathogens. In the present study, we identify and characterize a synergistic interaction of broad-spectrum nitroreductase-activated prodrugs 5-nitrofurans, with a secondary bile salt, Sodium Deoxycholate (DOC) in growth inhibition and killing of enterobacteria. Results Using checkerboard assay, we show that combination of nitrofuran furazolidone (FZ) and DOC generates a profound synergistic effect on growth inhibition in several enterobacterial species including Escherichia coli, Salmonella enterica, Citrobacter gillenii and Klebsiella pneumoniae. The Fractional Inhibitory Concentration Index (FICI) for DOC-FZ synergy ranges from 0.125 to 0.35 that remains unchanged in an ampicillin-resistant E. coli strain containing a β-lactamase-producing plasmid. Findings from the time-kill assay further highlight the synergy with respect to bacterial killing in E. coli and Salmonella. We further characterize the mechanism of synergy in E. coli K12, showing that disruption of the tolC or acrA genes that encode components of multidrug efflux pumps causes, respectively, a complete or partial loss, of the DOC-FZ synergy. This finding indicates the key role of TolC-associated efflux pumps in the DOC-FZ synergy. Overexpression of Nitric Oxide-detoxifying enzyme Hmp results in a three-fold increase in FICI for DOC-FZ interaction, suggesting a role of nitric oxide in the synergy. We further demonstrate that DOC-FZ synergy is largely independent of NfsA and NfsB, the two major activation enzymes of the nitrofuran prodrugs. Conclusions This study is to our knowledge the first report of nitrofuran-deoxycholate synergy against Gram-negative bacteria, offering potential applications in antimicrobial therapeutics. The mechanism of DOC-FZ synergy involves FZ-mediated inhibition of TolC-associated efflux pumps that normally remove DOC from bacterial cells. One possible route contributing to that effect is via FZ-mediated nitric oxide production.
dc.description.confidentialfalse
dc.edition.editionDecember 2020
dc.identifier.citationLe VVH, Olivera C, Spagnuolo J, Davies I, Rakonjac J. (2019). <i>In vitro</i> synergy between Sodium Deoxycholate and Furazolidone against Enterobacteria via Inhibition of Multidrug Efflux Pumps. BMC Microbiology. 20. 1.
dc.identifier.doi10.1101/518050
dc.identifier.elements-typejournal-article
dc.identifier.issn1471-2180
dc.identifier.number5
dc.identifier.piis12866-019-1668-3
dc.identifier.urihttps://mro.massey.ac.nz/handle/10179/70486
dc.languageEnglish
dc.publisherBioMed Central Ltd
dc.publisher.urihttps://bmcmicrobiol.biomedcentral.com/articles/10.1186/s12866-019-1668-3
dc.relation.isPartOfBMC Microbiology
dc.rights(c) 2020 The Author/s
dc.rightsCC BY 4.0
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectAntimicrobial combination
dc.subjectEnterobacteria
dc.subjectFurazolidone
dc.subjectNitrofurans
dc.subjectSodium Deoxycholate
dc.subjectSynergy
dc.titleIn vitro synergy between sodium deoxycholate and furazolidone against enterobacteria
dc.typeJournal article
pubs.elements-id440369
pubs.organisational-groupOther
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