The Role of ABC Transporters in Drug-Resistant Leishmania

Coelho, Adriano C.; Cotrim, Paulo C.

doi:10.1007/978-3-319-74186-4_11

Cited by 3 publications

(9 citation statements)

References 152 publications

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“…The ATP-binding cassette (ABC) transporters comprise a superfamily of transmembrane proteins that are involved in the transport of different molecules, from ions to large polypeptides, which have been largely recognized by their activity as drug efflux pumps [ 72 ]. In Leishmania spp., ABC transporters present high diversity and several of them have been mainly implicated in drug resistance [ 73 ]. Indeed, overexpression of ABC transporters is involved with miltefosine extrusion in resistant parasites [ 74 , 75 ].…”

Section: Resultsmentioning

confidence: 99%

In-Depth Quantitative Proteomics Characterization of In Vitro Selected Miltefosine Resistance in Leishmania infantum

et al. 2022

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Visceral leishmaniasis (VL) is a neglected disease caused by Leishmania parasites. Although significant morbidity and mortality in tropical and subtropical regions of the world are associated with VL, the low investment for developing new treatment measures is chronic. Moreover, resistance and treatment failure are increasing for the main medications, but the emergence of resistance phenotypes is poorly understood at the protein level. Here, we analyzed the development of resistance to miltefosine upon experimental selection in a L. infantum strain. Time to miltefosine resistance emergence was ~six months and label-free quantitative mass-spectrometry-based proteomics analyses revealed that this process involves a remodeling of components of the membrane and mitochondrion, with significant increase in oxidative phosphorylation complexes, particularly on complex IV and ATP synthase, accompanied by increased energy metabolism mainly dependent on β-oxidation of fatty acids. Proteins canonically involved in ROS detoxification did not contribute to the resistant process whereas sterol biosynthesis enzymes could have a role in this development. Furthermore, changes in the abundance of proteins known to be involved in miltefosine resistance such as ABC transporters and phospholipid transport ATPase were detected. Together, our data show a more complete picture of the elements that make up the miltefosine resistance phenotype in L. infantum.

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Section: Resultsmentioning

confidence: 99%

In-Depth Quantitative Proteomics Characterization of In Vitro Selected Miltefosine Resistance in Leishmania infantum

et al. 2022

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“…Conversely, our examination unveiled that the intracellular amastigote form displayed a diminished susceptibility to ML treatment, characterized by lower susceptibility indices and RRs in contrast to the extracellular forms. One of the fundamental determinants of our limited understanding of drug resistance in Leishmania is that most studies have only focused on the promastigote, the clinically irrelevant form of the parasites ( 20 ). Despite its shortcomings, the experimental induction of drug resistance in promastigotes is considered less challenging when compared to the intracellular forms.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, Tong et al ( 22 ) revealed that BEA resensitizes C. albicans , Aspergillus fumigatus , and Cryptococcus neoformans against numerous azoles and could reverse multidrug resistance in T. urticae ( 23 ). ABC transporters are pivotal in the process of drug efflux across various organisms, including Leishmania parasites ( 20 ). These ubiquitous transmembrane proteins serve as versatile molecular pumps with the capacity to transport a diverse array of molecules, including drugs, across cellular membranes ( 20 ).…”

Section: Discussionmentioning

confidence: 99%

“…ABC transporters are pivotal in the process of drug efflux across various organisms, including Leishmania parasites ( 20 ). These ubiquitous transmembrane proteins serve as versatile molecular pumps with the capacity to transport a diverse array of molecules, including drugs, across cellular membranes ( 20 ). In this study, we analyzed the transcription dynamics of ABC transporters, which play a key role in reducing the bioavailability of drugs.…”

Section: Discussionmentioning

confidence: 99%

“…ABC transporters mediate resistance in Leishmania by the efflux of anti-parasitic agents ( 19 ). One way to overpower ABC transporter-controlled multidrug resistance (MDR) is to search for potent ABC transporter inhibitors capable of resensitizing the parasite to anti-microbial agents ( 20 ). The first attempts at this approach were recorded by Pérez-Victoria et al ( 19 ), who showed a flavonoid derivative with a high affinity for the cytosolic NBD overcomes the ABC transporter-mediated ML resistance in Leishmania .…”

Section: Introductionmentioning

confidence: 99%

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

Al Khoury,

Thoumi,

Tokajian

et al. 2024

Antimicrob Agents Chemother

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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 IC 50 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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Target-Based Rational Improvement Strategies and Pitfalls in Leishmania Drug Discovery

Gupta,

Goicoechea,

Vance

et al. 2023

Natural Product Based Drug Discovery Against Human Parasites

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The Role of ABC Transporters in Drug-Resistant Leishmania

Cited by 3 publications

References 152 publications

In-Depth Quantitative Proteomics Characterization of In Vitro Selected Miltefosine Resistance in Leishmania infantum

In-Depth Quantitative Proteomics Characterization of In Vitro Selected Miltefosine Resistance in Leishmania infantum

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

Target-Based Rational Improvement Strategies and Pitfalls in Leishmania Drug Discovery

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