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ABC transporter inhibition by beauvericin partially overcomes drug resistance in Leishmania tropica.
Al Khoury, Charbel; Thoumi, Sergio; Tokajian, Sima; Sinno, Aia; Nemer, Georges; El Beyrouthy, Mark; Rahy, Kelven.
Afiliación
  • Al Khoury C; Department of Natural Sciences, School of Arts and Sciences, Lebanese American University, Beirut, Lebanon.
  • Thoumi S; Department of Computer Science and Mathematics, Lebanese American University, Beirut, Lebanon.
  • Tokajian S; Department of Natural Sciences, School of Arts and Sciences, Lebanese American University, Byblos, Lebanon.
  • Sinno A; Department of Natural Sciences, School of Arts and Sciences, Lebanese American University, Beirut, Lebanon.
  • Nemer G; Division of Genomics and Translational Biomedicine, College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.
  • El Beyrouthy M; Department of Agriculture and Food Engineering, Holy Spirit University of Kaslik, Jounieh, Lebanon.
  • Rahy K; Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Byblos, Lebanon.
Antimicrob Agents Chemother ; 68(5): e0136823, 2024 May 02.
Article en En | MEDLINE | ID: mdl-38572959
ABSTRACT
Leishmaniasis is a neglected tropical disease infecting the world's poorest populations. 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 Leishmania tropica 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 L. tropica 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 Leishmania tropica. The IC50 values, following BEA treatment, were significantly reduced from 30.83, 48.17, and 16.83 µM using ML to 8.14, 11.1, and 7.18 µM when using a combinatorial treatment (ML + BEA) against promastigotes, axenic amastigotes, and intracellular amastigotes, respectively. We also demonstrated a favorable BEA-binding enthalpy to L. tropica ABC transporter compared to ML. Our study revealed that BEA partially reverses the resistance development of L. tropica to ML by blocking the alternate ATP hydrolysis cycle.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fosforilcolina / Leishmania tropica / Resistencia a Medicamentos / Transportadoras de Casetes de Unión a ATP / Depsipéptidos / Simulación del Acoplamiento Molecular / Antiprotozoarios Límite: Humans Idioma: En Revista: Antimicrob Agents Chemother Año: 2024 Tipo del documento: Article País de afiliación: Líbano Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fosforilcolina / Leishmania tropica / Resistencia a Medicamentos / Transportadoras de Casetes de Unión a ATP / Depsipéptidos / Simulación del Acoplamiento Molecular / Antiprotozoarios Límite: Humans Idioma: En Revista: Antimicrob Agents Chemother Año: 2024 Tipo del documento: Article País de afiliación: Líbano Pais de publicación: Estados Unidos