{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T14:55:05Z","timestamp":1787756105176,"version":"build-2784847793"},"reference-count":70,"publisher":"American Society for Microbiology","issue":"2","license":[{"start":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T00:00:00Z","timestamp":1770163200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T00:00:00Z","timestamp":1770163200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01 AI27711"],"award-info":[{"award-number":["R01 AI27711"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R56 AI132682"],"award-info":[{"award-number":["R56 AI132682"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2026,2,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      <jats:italic toggle=\"yes\">Mycobacterium abscessus,<\/jats:italic>\n                      a rapidly growing nontuberculous mycobacterium, causes chronic pulmonary infections that are difficult to treat due to extensive intrinsic drug resistance. Through high-content screening of 786 FDA-approved drugs against intracellular\n                      <jats:italic toggle=\"yes\">M. abscessus<\/jats:italic>\n                      in human THP-1 macrophages, we identified naftifine, an antifungal allylamine, as a novel antimycobacterial agent with dual-acting therapeutic mechanisms. Naftifine demonstrated potent activity against reference strains and multidrug-resistant clinical isolates. It showed enhanced efficacy in intracellular environments compared to axenic culture, indicating significant host-directed effects. Mechanistic investigations revealed that naftifine operates through a unique dual mechanism. It directly targets bacteria by inhibiting MmpL3 (MAB_4508), the essential mycolic acid transporter, and modulates host immunity through autophagy activation via the mTOR pathway suppression. Whole-genome sequencing of spontaneous naftifine-resistant mutants identified point mutations (S302T and V299G) in MmpL3. Complementation studies confirmed MmpL3 as the primary molecular target. Cross-resistance analysis with other MmpL3 inhibitors (BM212 and AU1235) validated this target identification. Notably, naftifine represents the first MmpL3 inhibitor demonstrated to induce autophagy, distinguishing it from other MmpL3-targeting compounds. Naftifine-induced autophagy enhanced macrophage-mediated bacterial clearance and reduced infection-associated necrosis, improving host cell survival.\n                      <jats:italic toggle=\"yes\">In vivo<\/jats:italic>\n                      studies demonstrated a significant reduction of pulmonary and splenic bacterial burden with reduced lung inflammation. Furthermore, naftifine exhibited synergistic activity with \u03b2-lactam antibiotics without antagonizing other clinically used antibiotics. This is the first report demonstrating the unique combination of MmpL3 inhibition and autophagy induction by a single compound against\n                      <jats:italic toggle=\"yes\">M. abscessus<\/jats:italic>\n                      , establishing naftifine as a promising dual-action therapeutic candidate for treating multidrug-resistant infections.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/aac.01105-25","type":"journal-article","created":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T14:00:23Z","timestamp":1768399223000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":2,"title":["Protective mechanism of action of the antifungal drug naftifine against\n                    <i>Mycobacterium abscessus<\/i>\n                    infection"],"prefix":"10.1128","volume":"70","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6125-3544","authenticated-orcid":false,"given":"Jia","family":"Wang","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/016tfm930","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Immunology, University of Texas Medical Branch","place":["Galveston, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruchi","family":"Paroha","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/016tfm930","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Immunology, University of Texas Medical Branch","place":["Galveston, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Sha","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/016tfm930","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Immunology, 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