ABC transporter inhibition by beauvericin partially overcomes drug resistance in Leishmania tropica

• Published in: Antimicrobial agents and chemotherapy 2024-05, Vol.68 (5), p.e0136823-e0136823
• Main Authors: Al Khoury, Charbel, Thoumi, Sergio, Tokajian, Sima, Sinno, Aia, Nemer, Georges, El Beyrouthy, Mark, Rahy, Kelven
• Format: Article
• Language: English
• Subjects: Antimicrobial Chemotherapy; Antiprotozoal Agents - pharmacology; ATP-Binding Cassette Transporters - antagonists & inhibitors; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; Depsipeptides - pharmacology; Drug Resistance; Humans; Leishmania tropica - drug effects; Leishmania tropica - genetics; Mechanisms of Resistance; Molecular Docking Simulation; Phosphorylcholine - analogs & derivatives; Phosphorylcholine - pharmacology; Protozoan Proteins - antagonists & inhibitors; Protozoan Proteins - genetics; Protozoan Proteins - metabolism
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/aac.01368-23

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 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 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 . The IC 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 ABC transporter compared to ML. Our study revealed that BEA partially reverses the resistance development of to ML by blocking the alternate ATP hydrolysis cycle.