{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T13:28:25Z","timestamp":1787923705076,"version":"build-2784847793"},"reference-count":22,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"Key Research and Development Program of the Science and Technology Plan","award":["XZ202401ZY0052"],"award-info":[{"award-number":["XZ202401ZY0052"]}]},{"name":"Shanghai Agricultural Science and Technology Innovation Project","award":["2025-02-08-00-12-F00026"],"award-info":[{"award-number":["2025-02-08-00-12-F00026"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>In order to investigate the synergistic antibacterial effects of the novel FLT3 inhibitor G-749 in combination with colistin against Escherichia coli (E. coli).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The in vitro antibacterial activity of G-749 combined with colistin was evaluated by MIC using the broth microdilution method, followed by checkerboard synergy testing and time-kill assays. The in vivo efficacy was assessed in a murine thigh infection model using mcr-positive colistin-resistant strain M17GZZ15. Mechanistic studies employed propidium iodide (PI) and 4\u2032,6-diamidino-2-phenylindole (DAPI) staining to evaluate bacterial membrane integrity and nucleic acid content. The pharmacokinetic profile of G-749 was characterized in mice after a single oral dose of 100\u2005mg\/kg body weight.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>G-749 significantly potentiated colistin activity, reducing the MIC of colistin by 16- to 64-fold against susceptible E. coli ATCC25922 and by 8- to 32-fold against the resistant strain M17GZZ15. Time-kill assays revealed rapid bactericidal effects within 4\u2005h. In the murine thigh infection model, the combination therapy significantly reduced bacterial burdens compared with monotherapy (P\u200a&amp;lt;\u200a0.01). Mechanistic investigations showed enhanced PI uptake, indicating increased membrane permeability, and diminished DAPI fluorescence, suggesting intracellular nucleic acid leakage. Pharmacokinetic profiling of G-749 yielded a Cmax of 17.94\u2005mg\/L at Tmax 0.67\u2005h, an AUC0-24 of 44.91\u2005mg\u00b7h\/L, and an elimination half-life of 3.34\u2005h.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings establish G-749 as a potent colistin adjuvant that acts primarily by augmenting membrane disruption, with oxidative stress and energy suppression potentially contributing at higher concentrations, thereby improving antibacterial efficacy against Gram-negative bacteria. This multi-mechanistic and concentration-dependent synergistic profile offers a promising strategy to combat multidrug-resistant infections.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/jac\/dkag301","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T11:46:39Z","timestamp":1787139999000},"source":"Crossref","is-referenced-by-count":0,"title":["Study on the synergistic activity of G-749 and colistin against\n                    <i>Escherichia coli<\/i>"],"prefix":"10.1093","volume":"81","author":[{"given":"Tianle","family":"Pan","sequence":"first","affiliation":[{"name":"Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences , Shanghai 200241 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lian","family":"Liu","sequence":"additional","affiliation":[{"name":"Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences , Shanghai 200241 ,","place":["China"]},{"name":"China College of Animal Science and Technology, Yangtze University , Jingzhou, Hubei 434023 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruyue","family":"Huang","sequence":"additional","affiliation":[{"name":"Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences , Shanghai 200241 ,","place":["China"]},{"name":"China College of Animal Science and Technology, Yangtze University , Jingzhou, Hubei 434023 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mi","family":"Wang","sequence":"additional","affiliation":[{"name":"Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences , Shanghai 200241 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenzhong","family":"Fei","sequence":"additional","affiliation":[{"name":"Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences , Shanghai 200241 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingchun","family":"Liu","sequence":"additional","affiliation":[{"name":"Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences , Shanghai 200241 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,8,28]]},"reference":[{"key":"2026082805032064100_dkag301-B1","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1007\/s00228-015-1865-4","article-title":"A review on colistin nephrotoxicity","volume":"71","author":"Ordooei Javan","year":"2015","journal-title":"Eur J Clin Pharmacol"},{"key":"2026082805032064100_dkag301-B2","doi-asserted-by":"publisher","first-page":"e0196921","DOI":"10.1128\/aac.01969-21","article-title":"Transcriptomics reveals how minocycline-colistin synergy overcomes antibiotic resistance in multidrug-resistant Klebsiella pneumoniae","volume":"66","author":"Brennan-Krohn","year":"2022","journal-title":"Antimicrob Agents Chemother"},{"key":"2026082805032064100_dkag301-B3","doi-asserted-by":"publisher","first-page":"3227","DOI":"10.1093\/jac\/dkaf322","article-title":"Decrease in colistin resistance among young bovine and pig productions in France: relationship with colistin usage and stewardship measures","volume":"80","author":"Chauvin","year":"2025","journal-title":"J Antimicrob Chemother"},{"key":"2026082805032064100_dkag301-B4","doi-asserted-by":"publisher","first-page":"dlaf119","DOI":"10.1093\/jacamr\/dlaf119","article-title":"Prevalence of colistin resistance in multidrug-resistant Klebsiella pneumoniae recovered from clinical samples in Africa: a systematic review and meta-analysis","volume":"7","author":"Gashaw","year":"2025","journal-title":"JAC Antimicrob Resist"},{"key":"2026082805032064100_dkag301-B5","doi-asserted-by":"publisher","first-page":"e01487-20","DOI":"10.1128\/AAC.01172-20","article-title":"Activity of tigecycline or colistin in combination with zidovudine against Escherichia coli harboring tet(X) and mcr-1","volume":"65","author":"Zhou","year":"2021","journal-title":"Antimicrob Agents Chemother"},{"key":"2026082805032064100_dkag301-B6","doi-asserted-by":"publisher","first-page":"730241","DOI":"10.3389\/fphar.2021.730241","article-title":"G-749 Promotes receptor tyrosine kinase TYRO3 degradation and induces apoptosis in both colon cancer cell lines and Xenograft mouse models","volume":"12","author":"Kim","year":"2021","journal-title":"Front Pharmacol"},{"key":"2026082805032064100_dkag301-B7","doi-asserted-by":"publisher","first-page":"e07500","DOI":"10.1002\/slct.202507500","article-title":"Identification of FLT3 inhibitor G-749 as a promising antifungal lead through phenotypic screening and mechanism studies","volume":"11","author":"Liu","year":"2026","journal-title":"ChemistrySelect"},{"key":"2026082805032064100_dkag301-B8","author":"CLSI."},{"key":"2026082805032064100_dkag301-B9","doi-asserted-by":"publisher","first-page":"1040","DOI":"10.1038\/s41564-020-0723-z","article-title":"A broad spectrum antibiotic adjuvant reverses multidrug-resistant gram-negative pathogens","volume":"5","author":"Song","year":"2020","journal-title":"Nat Microbiol"},{"key":"2026082805032064100_dkag301-B10","doi-asserted-by":"publisher","first-page":"3701","DOI":"10.3390\/polym14173701","article-title":"Impact of diisocyanates on morphological and in vitro biological efficacy of eco-friendly castor-oil-based water-borne polyurethane dispersions","volume":"14","author":"Akram","year":"2022","journal-title":"Polymers (Basel)"},{"key":"2026082805032064100_dkag301-B11","doi-asserted-by":"publisher","first-page":"e0018422","DOI":"10.1128\/spectrum.00184-22","article-title":"Thymol increases sensitivity of clinical colistin-resistant gram-negative bacteria to colistin","volume":"10","author":"Yao","year":"2022","journal-title":"Microbiol Spectr"},{"key":"2026082805032064100_dkag301-B12","doi-asserted-by":"publisher","first-page":"1020652","DOI":"10.3389\/fmicb.2022.1020652","article-title":"Plumbagin resurrects colistin susceptibility against colistin-resistant Pseudomonas aeruginosa in vitro and in vivo","volume":"13","author":"Wang","year":"2022","journal-title":"Front Microbiol"},{"key":"2026082805032064100_dkag301-B13","doi-asserted-by":"publisher","first-page":"1895","DOI":"10.1093\/jac\/dkaa103","article-title":"Repositioning rafoxanide to treat gram-negative bacilli infections","volume":"75","author":"Mir\u00f3-Canturri","year":"2020","journal-title":"J Antimicrob Chemother"},{"key":"2026082805032064100_dkag301-B14","doi-asserted-by":"publisher","first-page":"106661","DOI":"10.1016\/j.fbio.2025.106661","article-title":"Glabridin pharmacodynamic activity toward gram-positive bacterial infections","volume":"68","author":"Chen","year":"2025","journal-title":"Food Biosci"},{"key":"2026082805032064100_dkag301-B15","doi-asserted-by":"publisher","first-page":"e0199222","DOI":"10.1128\/spectrum.01992-22","article-title":"Resveratrol increases sensitivity of clinical colistin-resistant Pseudomonas aeruginosa to colistin in vitro and in vivo","volume":"11","author":"Wang","year":"2023","journal-title":"Microbiol Spectr"},{"key":"2026082805032064100_dkag301-B16","doi-asserted-by":"publisher","first-page":"4243","DOI":"10.3390\/molecules28104243","article-title":"Application of rosmarinic acid with its derivatives in the treatment of microbial pathogens","volume":"28","author":"Kernou","year":"2023","journal-title":"Molecules"},{"key":"2026082805032064100_dkag301-B17","doi-asserted-by":"publisher","first-page":"36","DOI":"10.3390\/antibiotics12010036","article-title":"Synergistic effects of capric acid and colistin against colistin-susceptible and colistin-resistant enterobacterales","volume":"12","author":"Liu","year":"2022","journal-title":"Antibiotics (Basel)"},{"key":"2026082805032064100_dkag301-B18","doi-asserted-by":"publisher","first-page":"17946","DOI":"10.1038\/s41598-022-22189-x","article-title":"Intercellular interaction mechanisms promote diversity in intracellular ATP concentration in Escherichia coli populations","volume":"12","author":"Nakatani","year":"2022","journal-title":"Sci Rep"},{"key":"2026082805032064100_dkag301-B19","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1002\/jcp.10119","article-title":"Cellular response to oxidative stress: signaling for suicide and survival","volume":"192","author":"Martindale","year":"2002","journal-title":"J Cell Physiol"},{"key":"2026082805032064100_dkag301-B20","doi-asserted-by":"publisher","first-page":"3674","DOI":"10.1021\/acsnano.6b00181","article-title":"Antibacterial activity of Ti3C2Tx MXene","volume":"10","author":"Rasool","year":"2016","journal-title":"ACS Nano"},{"key":"2026082805032064100_dkag301-B21","doi-asserted-by":"publisher","first-page":"654","DOI":"10.1021\/acsbiomaterials.9b00932","article-title":"Self-assembled polyurethane capsules with selective antimicrobial activity against gram-negative E. coli","volume":"6","author":"Barman","year":"2020","journal-title":"ACS Biomater Sci Eng"},{"key":"2026082805032064100_dkag301-B22","doi-asserted-by":"publisher","first-page":"179","DOI":"10.3390\/antibiotics8040179","article-title":"Antibacterial effects of quinazolin-4(3H)-one functionalized-conjugated silver nanoparticles","volume":"8","author":"Masri","year":"2019","journal-title":"Antibiotics (Basel)"}],"container-title":["Journal of Antimicrobial Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jac\/article-pdf\/81\/9\/dkag301\/70826957\/dkag301.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jac\/article-pdf\/81\/9\/dkag301\/70826957\/dkag301.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T12:45:11Z","timestamp":1787921111000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jac\/article\/doi\/10.1093\/jac\/dkag301\/8772266"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,4]]},"references-count":22,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2026,8,4]]}},"URL":"https:\/\/doi.org\/10.1093\/jac\/dkag301","relation":{},"ISSN":["0305-7453","1460-2091"],"issn-type":[{"value":"0305-7453","type":"print"},{"value":"1460-2091","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,9]]},"published":{"date-parts":[[2026,8,4]]},"article-number":"dkag301"}}