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Miltefosine (ML) remains the primary oral drug against the cutaneous form of leishmaniasis. The ATP-binding cassette (ABC) transporters are key players in the xenobiotic efflux, and their inhibition could enhance the therapeutic index. In this study, the ability of beauvericin (BEA) to overcome ABC transporter-mediated resistance of\n              <jats:italic>Leishmania tropica<\/jats:italic>\n              to ML was assessed. In addition, the transcription profile of genes involved in resistance acquisition to ML was inspected. Finally, we explored the efflux mechanism of the drug and inhibitor. The efficacy of ML against all developmental stages of\n              <jats:italic>L. tropica<\/jats:italic>\n              in the presence or absence of BEA was evaluated using an absolute quantification assay. The expression of resistance genes was evaluated, comparing susceptible and resistant strains. Finally, the mechanisms governing the interaction between the ABC transporter and its ligands were elucidated using molecular docking and dynamic simulation. Relative quantification showed that the expression of the ABCG sub-family is mostly modulated by ML. In this study, we used BEA to impede resistance of\n              <jats:italic>Leishmania tropica<\/jats:italic>\n              . The IC\n              <jats:sub>50<\/jats:sub>\n              values, following BEA treatment, were significantly reduced from 30.83, 48.17, and 16.83 \u00b5M using ML to 8.14, 11.1, and 7.18 \u00b5M when using a combinatorial treatment (ML + BEA) against promastigotes, axenic amastigotes, and intracellular amastigotes, respectively. We also demonstrated a favorable BEA-binding enthalpy to\n              <jats:italic>L. tropica<\/jats:italic>\n              ABC transporter compared to ML. Our study revealed that BEA partially reverses the resistance development of\n              <jats:italic>L. tropica<\/jats:italic>\n              to ML by blocking the alternate ATP hydrolysis cycle.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/aac.01368-23","type":"journal-article","created":{"date-parts":[[2024,4,4]],"date-time":"2024-04-04T12:42:05Z","timestamp":1712234525000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":14,"title":["ABC transporter inhibition by beauvericin partially overcomes drug resistance in\n            <i>Leishmania tropica<\/i>"],"prefix":"10.1128","volume":"68","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0977-1242","authenticated-orcid":true,"given":"Charbel","family":"Al Khoury","sequence":"first","affiliation":[{"name":"Department of Natural Sciences, School of Arts and Sciences, Lebanese American University, Beirut, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergio","family":"Thoumi","sequence":"additional","affiliation":[{"name":"Department of Computer Science and Mathematics, Lebanese American University, Beirut, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sima","family":"Tokajian","sequence":"additional","affiliation":[{"name":"Department of Natural Sciences, School of Arts and Sciences, Lebanese American University, Byblos, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aia","family":"Sinno","sequence":"additional","affiliation":[{"name":"Department of Natural Sciences, School of Arts and Sciences, Lebanese American University, Beirut, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georges","family":"Nemer","sequence":"additional","affiliation":[{"name":"Division of Genomics and Translational Biomedicine, College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"El Beyrouthy","sequence":"additional","affiliation":[{"name":"Department of Agriculture and Food Engineering, Holy Spirit University of Kaslik, Jounieh, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelven","family":"Rahy","sequence":"additional","affiliation":[{"name":"Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Byblos, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2018.e00723"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.2807\/1560-7917.ES.2022.27.4.2002028"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2012.00083"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0000313"},{"key":"e_1_3_3_6_2","unstructured":"World Health Organization. 2023. 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