ABC transporter inhibition by beauvericin partially overcomes drug resistance in <i>Leishmania tropica</i>
<p dir="ltr">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...
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| مؤلفون آخرون: | , , , , , |
| منشور في: |
2024
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| _version_ | 1864513509849563136 |
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| author | Charbel Al Khoury (13167975) |
| author2 | Sergio Thoumi (19255920) Sima Tokajian (3559616) Aia Sinno (19255921) Georges Nemer (14152947) Mark El Beyrouthy (19255923) Kelven Rahy (19255926) |
| author2_role | author author author author author author |
| author_facet | Charbel Al Khoury (13167975) Sergio Thoumi (19255920) Sima Tokajian (3559616) Aia Sinno (19255921) Georges Nemer (14152947) Mark El Beyrouthy (19255923) Kelven Rahy (19255926) |
| author_role | author |
| dc.creator.none.fl_str_mv | Charbel Al Khoury (13167975) Sergio Thoumi (19255920) Sima Tokajian (3559616) Aia Sinno (19255921) Georges Nemer (14152947) Mark El Beyrouthy (19255923) Kelven Rahy (19255926) |
| dc.date.none.fl_str_mv | 2024-04-04T18:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1128/aac.01368-23 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/ABC_transporter_inhibition_by_beauvericin_partially_overcomes_drug_resistance_in_i_Leishmania_tropica_i_/26403256 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biomedical and clinical sciences Medical microbiology Pharmacology and pharmaceutical sciences Chemical sciences Medicinal and biomolecular chemistry Leishmania tropica leishmaniasis drug resistance ABC transporter |
| dc.title.none.fl_str_mv | ABC transporter inhibition by beauvericin partially overcomes drug resistance in <i>Leishmania tropica</i> |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <p dir="ltr">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 <i>Leishmania tropica</i> 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 <i>L. tropica</i> 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 <i>Leishmania tropica</i>. 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<i> L. tropica</i> to ML by blocking the alternate ATP hydrolysis cycle.</p><h2>Other Information</h2><p dir="ltr">Published in: Antimicrobial Agents and Chemotherapy<br>License: <a href="https://creativecommons.org/licenses/by/4.0/" target="_blank">https://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://doi.org/10.1128/aac.01368-23" target="_blank">https://doi.org/10.1128/aac.01368-23</a><a href="https://journals.asm.org/doi/10.1128/aac.01368-23#" target="_blank"><br></a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_ae6d61dbd070aeef4ef47463ddd9a0e7 |
| identifier_str_mv | 10.1128/aac.01368-23 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/26403256 |
| publishDate | 2024 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | ABC transporter inhibition by beauvericin partially overcomes drug resistance in <i>Leishmania tropica</i>Charbel Al Khoury (13167975)Sergio Thoumi (19255920)Sima Tokajian (3559616)Aia Sinno (19255921)Georges Nemer (14152947)Mark El Beyrouthy (19255923)Kelven Rahy (19255926)Biomedical and clinical sciencesMedical microbiologyPharmacology and pharmaceutical sciencesChemical sciencesMedicinal and biomolecular chemistryLeishmania tropicaleishmaniasisdrug resistanceABC transporter<p dir="ltr">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 <i>Leishmania tropica</i> 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 <i>L. tropica</i> 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 <i>Leishmania tropica</i>. 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<i> L. tropica</i> to ML by blocking the alternate ATP hydrolysis cycle.</p><h2>Other Information</h2><p dir="ltr">Published in: Antimicrobial Agents and Chemotherapy<br>License: <a href="https://creativecommons.org/licenses/by/4.0/" target="_blank">https://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://doi.org/10.1128/aac.01368-23" target="_blank">https://doi.org/10.1128/aac.01368-23</a><a href="https://journals.asm.org/doi/10.1128/aac.01368-23#" target="_blank"><br></a></p>2024-04-04T18:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1128/aac.01368-23https://figshare.com/articles/journal_contribution/ABC_transporter_inhibition_by_beauvericin_partially_overcomes_drug_resistance_in_i_Leishmania_tropica_i_/26403256CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/264032562024-04-04T18:00:00Z |
| spellingShingle | ABC transporter inhibition by beauvericin partially overcomes drug resistance in <i>Leishmania tropica</i> Charbel Al Khoury (13167975) Biomedical and clinical sciences Medical microbiology Pharmacology and pharmaceutical sciences Chemical sciences Medicinal and biomolecular chemistry Leishmania tropica leishmaniasis drug resistance ABC transporter |
| status_str | publishedVersion |
| title | ABC transporter inhibition by beauvericin partially overcomes drug resistance in <i>Leishmania tropica</i> |
| title_full | ABC transporter inhibition by beauvericin partially overcomes drug resistance in <i>Leishmania tropica</i> |
| title_fullStr | ABC transporter inhibition by beauvericin partially overcomes drug resistance in <i>Leishmania tropica</i> |
| title_full_unstemmed | ABC transporter inhibition by beauvericin partially overcomes drug resistance in <i>Leishmania tropica</i> |
| title_short | ABC transporter inhibition by beauvericin partially overcomes drug resistance in <i>Leishmania tropica</i> |
| title_sort | ABC transporter inhibition by beauvericin partially overcomes drug resistance in <i>Leishmania tropica</i> |
| topic | Biomedical and clinical sciences Medical microbiology Pharmacology and pharmaceutical sciences Chemical sciences Medicinal and biomolecular chemistry Leishmania tropica leishmaniasis drug resistance ABC transporter |