ArticleAntimicrobial agents and chemotherapy2011
Sitamaquine overcomes ABC-mediated resistance to miltefosine and antimony in Leishmania.
Article in Antimicrobial agents and chemotherapy, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 52 citations in OpenAlex.
- Miltefosine and emerging Leishmania (Mundinia) in Southeast Asia: Molecular insights, therapeutic challenges, and future strategic implementation.PLoS neglected tropical diseases · 2026Review
- Extending Thioflavin T Fluorescence Probe to 2-Ethenyl-benzothiazole Derivatives: Drug-like Quadruplex Ligands with Potent Antitrypanosomatid Activity.ACS infectious diseases · 2025Article
- Unravelling drug resistance in leishmaniasis: genomic adaptations and emerging therapies.Frontiers in molecular biosciences · 2025Review
- Repositioning of moxidectin: a promising approach in cutaneous leishmaniasis therapy.Parasite (Paris, France) · 2025Article
- Designing Antitrypanosomal and Antileishmanial BODIPY Derivatives: A Computational and In Vitro Assessment.Molecules (Basel, Switzerland) · 2024Article
- Genomic Insight of Leishmania Parasite: In-Depth Review of Drug Resistance Mechanisms and Genetic Mutations.ACS omega · 2024Review
- Antimony resistance and gene expression inParasitology · 2024Review
- PolyaromaticMolecules (Basel, Switzerland) · 2023Article
- Highlighting the interplay of microRNAs fromParasitology · 2021Review
- High resolution melting analysis and detection of Leishmania resistance: the role of multi drug resistance 1 gene.Genes and environment : the official journal of the Japanese Environmental Mutagen Society · 2021Article
- Antileishmanial Aminopyrazoles: Studies into Mechanisms and Stability of Experimental Drug Resistance.Antimicrobial agents and chemotherapy · 2020Article
- An Overview of Drug Resistance in Protozoal Diseases.International journal of molecular sciences · 2019Review
- Therapeutic Interventions for Countering Leishmaniasis and Chagas's Disease: From Traditional Sources to Nanotechnological Systems.Pathogens (Basel, Switzerland) · 2019Review
- G-Quadruplex Identification in the Genome of Protozoan Parasites Points to Naphthalene Diimide Ligands as New Antiparasitic Agents.Journal of medicinal chemistry · 2018Article
- Ruthenium-Clotrimazole complex has significant efficacy in the murine model of cutaneous leishmaniasis.Acta tropica · 2016Article
- Genomic Appraisal of the Multifactorial Basis for In Vitro Acquisition of Miltefosine Resistance in Leishmania donovani.Antimicrobial agents and chemotherapy · 2016Article
- From Drug Screening to Target Deconvolution: a Target-Based Drug Discovery Pipeline Using Leishmania Casein Kinase 1 Isoform 2 To Identify Compounds with Antileishmanial Activity.Antimicrobial agents and chemotherapy · 2016Article
- Design and synthesis of novel antileishmanial compounds.International journal of medicinal chemistry · 2015Article
- Chronic arsenic exposure and microbial drug resistance.Proceedings of the National Academy of Sciences of the United States of America · 2013Article
- Apoptotic marker expression in the absence of cell death in staurosporine-treated Leishmania donovani.Antimicrobial agents and chemotherapy · 2013Article
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Although oral miltefosine represented an important therapeutic advance in the treatment of leishmaniasis, the appearance of resistance remains a serious threat. LMDR1/LABCB4, a P-glycoprotein-like transporter included in the Leishmania ABC (ATP-binding cassette) family, was the first molecule shown to be involved in experimental miltefosine resistance. LMDR1 pumps drugs out of the parasite, thereby decreasing their intracellular accumulation. Sitamaquine, another promising oral drug for leishmaniasis, is currently in phase 2b clinical trials. The physicochemical features of this drug suggested to us that it could be considered for use as an LMDR1 inhibitor. Indeed, we report herein that nonleishmanicidal concentrations of sitamaquine reverse miltefosine resistance in a multidrug resistance Leishmania tropica line that overexpresses LMDR1. This reversal effect is due to modulation of the LMDR1-mediated efflux of miltefosine. In addition, sitamaquine is not a substrate of LMDR1, as this transporter does not affect sitamaquine accumulation or sensitivity in the parasite. Likewise, we show that ketoconazole, another oral leishmanicidal drug known to interact with ABC transporters, is also able to reverse LMDR1-mediated miltefosine resistance, although with a lower efficiency than sitamaquine. Molecular docking on a three-dimensional homology model of LMDR1 showed different preferential binding sites for each substrate-inhibitor pair, thus explaining this different behavior. Finally, we show that sitamaquine is also able to modulate the antimony resistance mediated by MRPA/LABCC3, another ABC transporter involved in experimental and clinical antimony resistance in this parasite. Taken together, these data suggest that the combination of sitamaquine with miltefosine or antimony could avoid the appearance of resistance mediated by these membrane transporters in Leishmania.
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