{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T00:27:36Z","timestamp":1793406456363,"version":"4.5.0"},"reference-count":37,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T00:00:00Z","timestamp":1764288000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Guangzhou Science and Technology Plan Project","award":["2024A04J3412"],"award-info":[{"award-number":["2024A04J3412"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,11,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Carbapenem- and colistin-resistant Escherichia coli co-carrying blaNDM-5 and mcr-1 represent a growing therapeutic challenge with limited treatment options. Fusidic acid (FA), a protein synthesis inhibitor, is inactive against Gram-negative bacteria because of its limited ability to permeate their outer membrane. This study aimed to evaluate whether colistin (CST) can restore FA activity against mcr-1-positive E. coli through membrane permeabilization-mediated synergy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>Three E. coli isolates carrying the blaNDM-5 and mcr-1 were subjected to antimicrobial susceptibility testing, checkerboard and time-kill assays, NPN uptake, intracellular FA accumulation analyses, and a murine thigh infection model. All isolates exhibited multidrug resistance but only low-level CST resistance (MIC 4\u20138\u00a0mg l\u22121). Checkerboard assays revealed strong synergy, with CST reducing FA minimum inhibitory concentrations (MICs) by\u00a0&amp;gt;1000-fold and restoring apparent susceptibility. Time-kill studies confirmed concentration-dependent synergistic bactericidal activity, achieving complete bacterial eradication when sub-MIC of FA was combined with CST. The tests for NPN uptake evolution and FA accumulation revealed that CST markedly increased membrane permeability and intracellular FA levels (5- to 8-fold). In the mouse thigh infection model, combination therapy with CST and FA at clinically equivalent doses produced a\u00a0\u22653.0-log10 cfu g\u22121 reduction relative to the control and a\u00a0&amp;gt;2.0-log10 cfu g\u22121 reduction compared with either monotherapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>CST markedly enhances FA activity against mcr-1-positive E. coli by compromising outer membrane integrity and facilitating intracellular antibiotic accumulation. This synergy highlights a rational combination approach to restore the efficacy of obsolete antibiotics for multidrug-resistant Gram-negative bacteria.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/jambio\/lxaf305","type":"journal-article","created":{"date-parts":[[2025,12,13]],"date-time":"2025-12-13T13:02:18Z","timestamp":1765630938000},"source":"Crossref","is-referenced-by-count":1,"title":["Repurposing fusidic acid through colistin-mediated membrane permeabilization against\n                    <i>Escherichia coli<\/i>\n                    co-harboring\n                    <i>mcr<\/i>\n                    -1 and\n                    <i>bla<\/i>\n                    NDM-5"],"prefix":"10.1093","volume":"136","author":[{"given":"Ting-Yin","family":"Lu","sequence":"first","affiliation":[{"name":"National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, College of Veterinary Medicine, South China Agricultural University , No. 483 Wushan Road, Tianhe District, Guangzhou 510642 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Hui","family":"Su","sequence":"additional","affiliation":[{"name":"National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, College of Veterinary Medicine, South China Agricultural University , No. 483 Wushan Road, Tianhe District, Guangzhou 510642 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng-Ting","family":"Tao","sequence":"additional","affiliation":[{"name":"Institute of Laboratory Animal Science, Jinan University , No. 601 Huangpu Avenue West, Tianhe District, Guangzhou 510632 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6882-5058","authenticated-orcid":false,"given":"Yu-Feng","family":"Zhou","sequence":"additional","affiliation":[{"name":"National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, College of Veterinary Medicine, South China Agricultural University , No. 483 Wushan Road, Tianhe District, Guangzhou 510642 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,12,15]]},"reference":[{"key":"2025122403125564600_bib1","doi-asserted-by":"crossref","first-page":"e00873","DOI":"10.1128\/AAC.00873-18","article-title":"Synergistic activity of colistin-containing combinations against colistin-resistant Enterobacteriaceae","volume":"62","author":"Brennan-Krohn","year":"2018","journal-title":"Antimicrob Agents Chemother"},{"key":"2025122403125564600_bib2","doi-asserted-by":"crossref","first-page":"4733","DOI":"10.1038\/s41467-024-49200-5","article-title":"Potent activity of polymyxin B is associated with long-lived super-stoichiometric accumulation mediated by weak-affinity binding to lipid a","volume":"15","author":"Buchholz","year":"2024","journal-title":"Nat Commun"},{"key":"2025122403125564600_bib3","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1128\/AAC.01354-12","article-title":"Population pharmacokinetics of fusidic acid: rationale for front-loaded dosing regimens due to autoinhibition of clearance","volume":"57","author":"Bulitta","year":"2013","journal-title":"Antimicrob Agents Chemother"},{"key":"2025122403125564600_bib4","doi-asserted-by":"crossref","first-page":"1220683","DOI":"10.3389\/fmicb.2023.1220683","article-title":"Polymyxin B and fusidic acid, a novel potent synergistic combination against Klebsiella pneumoniae and Escherichia coli isolates with polymyxin B resistance","volume":"14","author":"Chen","year":"2023","journal-title":"Front Microbiol"},{"key":"2025122403125564600_bib5","volume-title":"Methods for Determining Bactericidal Activity of Antimicrobial Agents; Approved Guideline. 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