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In the present study, we identify and characterize a synergistic interaction of broad-spectrum nitroreductase-activated prodrugs 5-nitrofurans, with a secondary bile salt, <jats:sc>s<\/jats:sc>odium <jats:sc>d<\/jats:sc>eoxycholate (DOC) in growth inhibition and killing of enterobacteria.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>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 <jats:italic>Escherichia coli<\/jats:italic>, <jats:italic>Salmonella enterica<\/jats:italic>, <jats:italic>Citrobacter gillenii<\/jats:italic> and <jats:italic>Klebsiella pneumoniae<\/jats:italic>. The Fractional Inhibitory Concentration Index (FICI) for DOC-FZ synergy ranges from 0.125 to 0.35 that remains unchanged in an ampicillin-resistant <jats:italic>E. coli<\/jats:italic> strain containing a \u03b2-lactamase-producing plasmid. Findings from the time-kill assay further highlight the synergy with respect to bacterial killing in <jats:italic>E. coli<\/jats:italic> and <jats:italic>Salmonella<\/jats:italic>.<\/jats:p>\n                <jats:p>We further characterize the mechanism of synergy in <jats:italic>E. coli<\/jats:italic> K12, showing that disruption of the <jats:italic>tolC<\/jats:italic> or <jats:italic>acrA<\/jats:italic> 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 <jats:sc>n<\/jats:sc>itric <jats:sc>o<\/jats:sc>xide-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.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>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.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12866-019-1668-3","type":"journal-article","created":{"date-parts":[[2020,1,6]],"date-time":"2020-01-06T19:03:05Z","timestamp":1578337385000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["In vitro synergy between sodium deoxycholate and furazolidone against enterobacteria"],"prefix":"10.1186","volume":"20","author":[{"given":"Vuong Van Hung","family":"Le","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catrina","family":"Olivera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian","family":"Spagnuolo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ieuan G.","family":"Davies","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6756-4682","authenticated-orcid":false,"given":"Jasna","family":"Rakonjac","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,1,6]]},"reference":[{"key":"1668_CR1","unstructured":"O\u2019Neill J. 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