{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T04:36:23Z","timestamp":1774067783957,"version":"3.50.1"},"reference-count":31,"publisher":"American Society for Microbiology","issue":"2","license":[{"start":{"date-parts":[[2016,2,1]],"date-time":"2016-02-01T00:00:00Z","timestamp":1454284800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2016,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Despite the existing treatment options for onychomycosis, there remains a strong demand for potent topical medications. ME1111 is a novel antifungal agent that is active against dermatophytes, has an excellent ability to penetrate human nails, and is being developed as a topical agent for onychomycosis. In the present study, we investigated its mechanism of action.\n                    <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Trichophyton mentagrophytes<\/jats:named-content>\n                    mutants with reduced susceptibility to ME1111 were selected in our laboratory, and genome sequences were determined for 3 resistant mutants. The inhibitory effect on a candidate target was evaluated by a spectrophotometric enzyme assay using mitochondrial fractions. Point mutations were introduced into candidate genes by a reverse genetics approach. Whole-genome analysis of the 3 selected mutants revealed point mutations in the structural regions of genes encoding subunits of succinate dehydrogenase (complex II). All of the laboratory-generated resistant mutants tested harbored a mutation in one of the subunits of succinate dehydrogenase (SdhB, SdhC, or SdhD). Most of the mutants showed cross-resistance to carboxin and boscalid, which are succinate dehydrogenase inhibitors. ME1111 strongly inhibited the succinate-2,6-dichlorophenolindophenol reductase reaction in\n                    <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Trichophyton rubrum<\/jats:named-content>\n                    and\n                    <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">T. mentagrophytes<\/jats:named-content>\n                    (50% inhibitory concentrations [IC\n                    <jats:sub>50<\/jats:sub>\n                    s] of 0.029 and 0.025 \u03bcg\/ml, respectively) but demonstrated only moderate inhibition of the same reaction in human cell lines. Furthermore, the target protein of ME1111 was confirmed by the introduction of point mutations causing the amino acid substitutions in SdhB, SdhC, and SdhD found in the laboratory-generated resistant mutants, which resulted in reduced susceptibility to ME1111. Thus, ME1111 is a novel inhibitor of the succinate dehydrogenase of\n                    <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Trichophyton<\/jats:named-content>\n                    species, and its mechanism of action indicates its selective profile.\n                  <\/jats:p>","DOI":"10.1128\/aac.01790-15","type":"journal-article","created":{"date-parts":[[2015,11,23]],"date-time":"2015-11-23T21:43:29Z","timestamp":1448315009000},"page":"873-880","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":28,"title":["Mechanism of Action of ME1111, a Novel Antifungal Agent for Topical Treatment of Onychomycosis"],"prefix":"10.1128","volume":"60","author":[{"given":"Sho","family":"Takahata","sequence":"first","affiliation":[{"name":"Meiji Seika Pharma Co., Ltd., Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natsuki","family":"Kubota","sequence":"additional","affiliation":[{"name":"Meiji Seika Pharma Co., Ltd., Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naomi","family":"Takei-Masuda","sequence":"additional","affiliation":[{"name":"Meiji Seika Pharma Co., Ltd., Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tsuyoshi","family":"Yamada","sequence":"additional","affiliation":[{"name":"Teikyo University Institute of Medical Mycology, Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mari","family":"Maeda","sequence":"additional","affiliation":[{"name":"Teikyo University Institute of Medical Mycology, Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohamed Mahdi","family":"Alshahni","sequence":"additional","affiliation":[{"name":"Graduate School of Medicine, Teikyo University, Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shigeru","family":"Abe","sequence":"additional","affiliation":[{"name":"Teikyo University Institute of Medical Mycology, Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuji","family":"Tabata","sequence":"additional","affiliation":[{"name":"Meiji Seika Pharma Co., Ltd., Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazunori","family":"Maebashi","sequence":"additional","affiliation":[{"name":"Meiji Seika Pharma Co., Ltd., Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1001\/archderm.1997.03890450124022"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1067\/mjd.2000.107754"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1067\/mjd.2000.104794"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2133.1995.tb02741.x"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaad.2012.10.013"},{"key":"e_1_3_2_7_2","first-page":"1124","article-title":"The efficacy and safety of tavaborole, a novel, boron-based pharmaceutical agent: phase 2 studies conducted for the topical treatment of toenail onychomycosis","volume":"13","author":"Toledo-Bahena ME","year":"2014","unstructured":"Toledo-Bahena ME, Bucko A, Ocampo-Candiani J, Herz-Ruelas ME, Jones TM, Jarratt MT, Pollak RA, Zane LT. 2014. The efficacy and safety of tavaborole, a novel, boron-based pharmaceutical agent: phase 2 studies conducted for the topical treatment of toenail onychomycosis. 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In vitro antifungal activity of and assessment of resistance to ME1111, a new antifungal agent for topical treatment of onychomycosis, abstr F-1587. Abstr 54th Intersci Conf Antimicrob Agents Chemother. American Society for Microbiology, Washington, DC."},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-5173(01)00989-9"},{"key":"e_1_3_2_18_2","volume-title":"Abstr 54th Intersci Conf Antimicrob Agents Chemother","author":"Hui X","year":"2014","unstructured":"Hui X, Maibach H. 2014. In vitro human nail plate penetration of a novel antifungal agent, ME1111, abstr F-1588. Abstr 54th Intersci Conf Antimicrob Agents Chemother. American Society for Microbiology, Washington, DC."},{"key":"e_1_3_2_19_2","volume-title":"Abstr 54th Intersci Conf Antimicrob Agents Chemother","author":"Tabata Y","year":"2014","unstructured":"Tabata Y, Nomoto M, Chikada T, Kubota N, Takei-Masuda N, Takahata S, Maebashi K. 2014. In vitro and in vivo nail penetration of ME1111, a novel antifungal agent for topical treatment of onychomycosis, abstr F-1589. Abstr 54th Intersci Conf Antimicrob Agents Chemother. American Society for Microbiology, Washington, DC."},{"key":"e_1_3_2_20_2","volume-title":"Abstr 54th Intersci Conf Antimicrob Agents Chemother","author":"Ago K","year":"2014","unstructured":"Ago K, Nomoto M, Chikada T, Uchida M, Tsuchiya T, Shibasaki S, Maebashi K, Hiratsuka K. 2014. Nonclinical safety assessment of ME1111, a novel antifungal agent for the topical treatment of onychomycosis, abstr F-1593. Abstr 54th Intersci Conf Antimicrob Agents Chemother. American Society for Microbiology, Washington, DC."},{"key":"e_1_3_2_21_2","unstructured":"Takahata S Tabata Y Takei-Masuda N Kubota N Maebashi K. 2014. Mechanism of action of ME1111 a new antifungal agent for topical treatment of onychomycosis abstr F-1585. Abstr 54th Intersci Conf Antimicrob Agents Chemother. 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