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In this study, we investigated the therapeutic efficacy of the rifamycin derivative, rifalazil (RLZ) (also known as KRM-1648), in an advanced <jats:italic>M<\/jats:italic>. <jats:italic>ulcerans<\/jats:italic> infection model. Six-week-old female BALB\/c mice were infected with 3.25 x 10<jats:sup>4<\/jats:sup> colony-forming units (CFU) of <jats:italic>M<\/jats:italic>. <jats:italic>ulcerans<\/jats:italic> subcutaneously into the bilateral hind footpads. At 33 days post-infection, when the footpads exhibited significant redness and swelling, mice were treated orally with 5 or 10 mg\/kg of RLZ for up to 15 weeks. Mice were followed for an additional 15 weeks following treatment cessation. Untreated mice exhibited a progressive increase in footpad redness, swelling, and erosion over time, and all untreated mice reached to endpoint within 5\u20138 weeks post-bacterial injection. In the RLZ-treated mice, footpad redness and swelling and general condition improved or completely healed, and no recurrence occurred following treatment cessation. After 3 weeks of treatment, the CFU counts from the footpads of recovered RLZ-treated mice showed a 10<jats:sup>4<\/jats:sup> decrease compared with those of untreated mice. We observed a further reduction in CFU counts to the detection limit following 6 to 15 weeks of treatment, which did not increase 15 weeks after discontinuing the treatment. Histopathologically, bacteria in the treated mice became fragmented one week after RLZ-treatment. At the final point of the experiment, all the treated mice (5mg\/kg\/day; n = 6, 10mg\/kg\/day; n = 7) survived and had no signs of <jats:italic>M<\/jats:italic>. <jats:italic>ulcerans<\/jats:italic> infection. These results indicate that the rifamycin analogue, RLZ, is efficacious in the treatment of an advanced <jats:italic>M<\/jats:italic>. <jats:italic>ulcerans<\/jats:italic> infection mouse model.<\/jats:p>","DOI":"10.1371\/journal.pone.0274742","type":"journal-article","created":{"date-parts":[[2022,10,6]],"date-time":"2022-10-06T17:49:53Z","timestamp":1665078593000},"page":"e0274742","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Therapeutic efficacy of rifalazil (KRM-1648) in a M. ulcerans-induced Buruli ulcer mouse model"],"prefix":"10.1371","volume":"17","author":[{"given":"Hanako","family":"Fukano","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazue","family":"Nakanaga","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0943-4115","authenticated-orcid":true,"given":"Masamichi","family":"Goto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mitsunori","family":"Yoshida","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Norihisa","family":"Ishii","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3132-0715","authenticated-orcid":true,"given":"Yoshihiko","family":"Hoshino","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2022,10,6]]},"reference":[{"key":"pone.0274742.ref001","unstructured":"Buruli ulcer (Mycobacterium ulcerans infection). 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