{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T01:12:21Z","timestamp":1775869941869,"version":"3.50.1"},"reference-count":44,"publisher":"Microbiology Society","issue":"2","license":[{"start":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T00:00:00Z","timestamp":1739232000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Massey University-MBIE PSAF II","award":["MU001985"],"award-info":[{"award-number":["MU001985"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,2,11]]},"abstract":"<jats:p>\n                    The combined application of furazolidone and vancomycin has previously been shown to be synergistic against Gram-negative pathogens, with great therapeutic promise. However, the emergence and mechanism of resistance to this antibiotic combination have not been characterized. To fill this gap, we here selected\n                    <jats:italic>Escherichia coli<\/jats:italic>\n                    progeny for growth on the furazolidone\u2013vancomycin combination at the concentration where the parent was sensitive. We show that selected clones were associated with increased resistance to neither, only one drug, or both furazolidone and vancomycin, but in all cases were associated with a decrease in the growth inhibition synergy. Using whole-genome sequencing, we identified various gene mutations in the resistant mutants. We further investigated the mechanism behind the most frequently arising mutations, those in the riboflavin biosynthesis genes\n                    <jats:italic>ribB<\/jats:italic>\n                    and\n                    <jats:italic>ribE<\/jats:italic>\n                    , that represent novel mutations causing furazolidone resistance and diminished vancomycin\u2013furazolidone synergy. It was found that these\n                    <jats:italic>ribB\/ribE<\/jats:italic>\n                    mutations act predominantly by decreasing the activity of the NfsA and NfsB nitroreductases. The emergence of the\n                    <jats:italic>ribB<\/jats:italic>\n                    \/\n                    <jats:italic>ribE<\/jats:italic>\n                    mutations imposes a significant fitness cost on bacterial growth. Surprisingly, supplementing the medium with riboflavin, which compensates for the affected riboflavin biosynthesis pathway, could restore the normal growth of the\n                    <jats:italic>ribB<\/jats:italic>\n                    \/\n                    <jats:italic>ribE<\/jats:italic>\n                    mutants while having no effects on the furazolidone resistance phenotype. Searching the\n                    <jats:italic>ribB\/ribE<\/jats:italic>\n                    mutations in the public sequencing database detects the presence of the furazolidone-resistance-conferring\n                    <jats:italic>ribE<\/jats:italic>\n                    mutations (TKAG\n                    <jats:sup>131\u2013134<\/jats:sup>\n                    deletion or duplication) in clinical isolates from different countries. Hypotheses explaining why these\n                    <jats:italic>ribE<\/jats:italic>\n                    mutations were found in clinical isolates despite having poor fitness were further discussed.\n                  <\/jats:p>","DOI":"10.1099\/mgen.0.001356","type":"journal-article","created":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T11:18:29Z","timestamp":1739272709000},"source":"Crossref","is-referenced-by-count":1,"title":["Mutations in the riboflavin biosynthesis pathway confer resistance to furazolidone and abolish the synergistic interaction between furazolidone and vancomycin in Escherichia coli"],"prefix":"10.1099","volume":"11","author":[{"given":"Hannah","family":"Wykes","sequence":"first","affiliation":[{"name":"School of Food Technology and Natural Sciences, Massey University, Palmerston North, New Zealand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9576-5246","authenticated-orcid":false,"given":"Vuong Van Hung","family":"Le","sequence":"additional","affiliation":[{"name":"Living Systems Institute, University of Exeter, Exeter, UK"},{"name":"School of Food Technology and Natural Sciences, Massey University, Palmerston North, New Zealand"},{"name":"Faculty of Health and Life Sciences, University of Exeter, Exeter, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6756-4682","authenticated-orcid":false,"given":"Jasna","family":"Rakonjac","sequence":"additional","affiliation":[{"name":"School of Food Technology and Natural Sciences, Massey University, Palmerston North, New Zealand"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"345","reference":[{"key":"R1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2016.05.015"},{"key":"R2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01768-09"},{"key":"R3","doi-asserted-by":"publisher","DOI":"10.15252\/msb.20156098"},{"key":"R4","doi-asserted-by":"publisher","DOI":"10.1186\/s12866-019-1668-3"},{"key":"R5","doi-asserted-by":"publisher","DOI":"10.1099\/jmm.0.001304"},{"key":"R6","doi-asserted-by":"publisher","DOI":"10.1002\/0471142727.mb0117s79"},{"key":"R7","doi-asserted-by":"publisher","DOI":"10.1038\/msb4100050"},{"key":"R8","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.120163297"},{"key":"R9","doi-asserted-by":"publisher","DOI":"10.1093\/dnares\/dsi012"},{"key":"R10","volume-title":"Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; 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