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Here, we examined the efficacy of ivermectin, moxidectin (MOX), afoxolaner, and permethrin against all stages of <jats:italic>Leishmania tropica<\/jats:italic> and THP-1 cells. We also assessed the potential for resistance acquisition after 15 rounds of artificial selection. To elucidate the mode of action of MOX, we employed RNA sequencing, molecular dynamics simulation, and chloride flux assays. Additionally, we evaluated the therapeutic index of MOX using the <jats:italic>Galleria mellonella<\/jats:italic> infection model. MOX demonstrated the highest selectivity index against leishmaniasis (promastigotes: 0.58\u00a0\u03bcM; amastigotes: 0.96\u00a0\u03bcM; host cells: 60.29\u00a0\u03bcM). Moreover, MOX exhibited the lowest resistance acquisition in both promastigotes and intracellular amastigotes after 15 rounds of artificial selection, with resistance ratios of 17.23 and 4.59, respectively. Post-exposure to MOX, differential gene expression profiles showed both stage-specific and stage-unspecific enrichment of gene families involved in crucial biological processes. Moreover, molecular dynamics simulations revealed a potential neutralizing effect of MOX on the chloride channel of <jats:italic>L. tropica<\/jats:italic>. Specifically, MOX binds to the selectivity filter, potentially disrupting the osmotic equilibrium and thereby killing the parasite. The <jats:italic>in vivo<\/jats:italic> introduction of MOX significantly inhibited the growth of <jats:italic>L. tropica<\/jats:italic> in <jats:italic>G. mellonella<\/jats:italic> larvae, resulting in decreased rates of mortality and melanization. These findings indicate that MOX is a promising candidate for the treatment of <jats:italic>L. tropica<\/jats:italic> infections, warranting further investigation and potential consideration for clinical use<jats:italic>.<\/jats:italic>\n\t\t\t\t<\/jats:p>","DOI":"10.1051\/parasite\/2025035","type":"journal-article","created":{"date-parts":[[2025,7,4]],"date-time":"2025-07-04T07:51:53Z","timestamp":1751615513000},"page":"42","source":"Crossref","is-referenced-by-count":1,"title":["Repositioning of moxidectin: a promising approach in cutaneous leishmaniasis therapy"],"prefix":"10.1051","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7444-5617","authenticated-orcid":false,"given":"Lynn","family":"Al Samra","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamad","family":"El Nahas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilham","family":"Mneimneh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sima","family":"Tokajian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georges","family":"Nemer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aia","family":"Sinno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelven","family":"Rahy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergio","family":"Thoumi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zahraa","family":"Zibara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmad","family":"El Khatib","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dalal","family":"Sabbagh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3577-6979","authenticated-orcid":false,"given":"Jacques","family":"Guillot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louna","family":"Karam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lazo","family":"Ali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruqaya","family":"Baghdadi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0977-1242","authenticated-orcid":false,"given":"Charbel","family":"Al Khoury","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"250","published-online":{"date-parts":[[2025,7,4]]},"reference":[{"key":"R1","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","volume":"1","author":"Abraham","year":"2015","journal-title":"SoftwareX"},{"key":"R2","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.rvsc.2022.10.012","volume":"153","author":"Al Khoury","year":"2022","journal-title":"Research in Veterinary Science"},{"key":"R3","doi-asserted-by":"crossref","first-page":"10865","DOI":"10.1038\/s41598-021-89622-5","volume":"11","author":"Al Khoury","year":"2021","journal-title":"Scientific Reports"},{"key":"R4","doi-asserted-by":"crossref","first-page":"1368","DOI":"10.1128\/aac.01368-23","volume":"68","author":"Al Khoury","year":"2024","journal-title":"Antimicrobial Agents and Chemotherapy"},{"key":"R5","doi-asserted-by":"crossref","first-page":"232","DOI":"10.3390\/metabo14040232","volume":"14","author":"Al Khoury","year":"2024","journal-title":"Metabolites"},{"key":"R6","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1186\/1756-3305-6-94","volume":"6","author":"Alasaad","year":"2013","journal-title":"Parasites & Vectors"},{"key":"R7","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1002\/bdd.572","volume":"28","author":"Al-Azzam","year":"2007","journal-title":"Biopharmaceutics & Drug Disposition"},{"key":"R8","unstructured":"Andrews S. 2022. 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