ArticleAntimicrobial agents and chemotherapy2006
Combination of suboptimal doses of inhibitors targeting different domains of LtrMDR1 efficiently overcomes resistance of Leishmania spp. to Miltefosine by inhibiting drug efflux.
Article in Antimicrobial agents and chemotherapy, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 47 citations in OpenAlex.
- Roles of efflux pumps and nitroreductases in metronidazole-resistant Trichomonas vaginalis.Parasitology research · 2025Article
- In-Depth Quantitative Proteomics Characterization of In Vitro Selected Miltefosine Resistance inProteomes · 2022Article
- Antimicrobial Secretions of Toads (Anura, Bufonidae): Bioactive Extracts and Isolated Compounds against Human Pathogens.Antibiotics (Basel, Switzerland) · 2020Review
- Antileishmanial Aminopyrazoles: Studies into Mechanisms and Stability of Experimental Drug Resistance.Antimicrobial agents and chemotherapy · 2020Article
- Phenotypic adaptations of Leishmania donovani to recurrent miltefosine exposure and impact on sand fly infection.Parasites & vectors · 2020Article
- Investigation of the pathways related to intrinsic miltefosine tolerance in Leishmania (Viannia) braziliensis clinical isolates reveals differences in drug uptake.International journal for parasitology. Drugs and drug resistance · 2019Article
- Identification and Characterization of the Entamoeba Histolytica Rab8a Binding Protein: A Cdc50 Homolog.International journal of molecular sciences · 2018Article
- Autophagic-related cell death of Trypanosoma brucei induced by bacteriocin AS-48.International journal for parasitology. Drugs and drug resistance · 2018Article
- Different Mutations in a P-type ATPase Transporter in Leishmania Parasites are Associated with Cross-resistance to Two Leading Drugs by Distinct Mechanisms.PLoS neglected tropical diseases · 2016Article
- New Approaches to Overcome Transport Related Drug Resistance in Trypanosomatid Parasites.Frontiers in pharmacology · 2016Review
- The Oral Antimalarial Drug Tafenoquine Shows Activity against Trypanosoma brucei.Antimicrobial agents and chemotherapy · 2015Article
- Untargeted metabolomic analysis of miltefosine action in Leishmania infantum reveals changes to the internal lipid metabolism.International journal for parasitology. Drugs and drug resistance · 2014Article
- Metabolic reconstruction identifies strain-specific regulation of virulence in Toxoplasma gondii.Molecular systems biology · 2013Article
- Therapeutic switching in leishmania chemotherapy: a distinct approach towards unsatisfied treatment needs.Journal of parasitic diseases : official organ of the Indian Society for Parasitology · 2011Article
- Sitamaquine overcomes ABC-mediated resistance to miltefosine and antimony in Leishmania.Antimicrobial agents and chemotherapy · 2011Article
- Use of antimony in the treatment of leishmaniasis: current status and future directions.Molecular biology international · 2011Article
- Drug resistance in visceral leishmaniasis.Journal of biomedicine & biotechnology · 2010Review
- Characterization of an ABCG-like transporter from the protozoan parasite Leishmania with a role in drug resistance and transbilayer lipid movement.Antimicrobial agents and chemotherapy · 2008Article
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Authors and funding
12 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Miltefosine (hexadecylphosphocholine) is the first orally active drug approved for the treatment of leishmaniasis. We have previously shown the involvement of LtrMDR1, a P-glycoprotein-like transporter belonging to the ATP-binding cassette superfamily, in miltefosine resistance in Leishmania. Here we show that overexpression of LtrMDR1 increases miltefosine efflux, leading to a decrease in drug accumulation in the parasites. Although LtrMDR1 modulation might be an efficient way to overcome this resistance, a main drawback associated with the use of P-glycoprotein inhibitors is related to their intrinsic toxicity. In order to diminish possible side effects, we have combined suboptimal doses of modulators targeting both the cytosolic and transmembrane domains of LtrMDR1. Preliminary structure-activity relationships have allowed us to design a new and potent flavonoid derivative with high affinity for the cytosolic nucleotide-binding domains. As modulators directed to the transmembrane domains, we have selected one of the most potent dihydro-beta-agarofuran sesquiterpenes described, and we have also studied the effects of two of the most promising, latest-developed modulators of human P-glycoprotein, zosuquidar (LY335979) and elacridar (GF120918). The results show that this combinatorial strategy efficiently overcomes P-glycoprotein-mediated parasite miltefosine resistance by increasing intracellular miltefosine accumulation without any side effect in the parental, sensitive, Leishmania line and in different mammalian cell lines.
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