ArticleParasites & vectors2014
The overexpression of genes of thiol metabolism contribute to drug resistance in clinical isolates of visceral leishmaniasis (kala azar) in India.
Article in Parasites & vectors, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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11 citing papers in PubMed, 29 citations in OpenAlex.
- Visceral leishmaniasis: an integrated review of resistance mechanisms, host immunometabolism, and next generation therapeutics.Inflammopharmacology · 2026Review
- Antimony resistance and gene expression inParasitology · 2024Review
- Translational reprogramming as a driver of antimony-drug resistance in Leishmania.Nature communications · 2023Article
- Antimony resistance mechanism in genetically different clinical isolates of Indian Kala-azar patients.Frontiers in cellular and infection microbiology · 2022Article
- Editorial: Signaling in stress sensing and resistance in parasitic protozoa.Frontiers in cellular and infection microbiology · 2022Article
- Mutations in an Aquaglyceroporin as a Proven Marker of Antimony Clinical Resistance in the Parasite Leishmania donovani.Clinical infectious diseases : an official publication of the Infectious Diseases Society of America · 2021Article
- Metabolite Biomarkers ofCells · 2021Article
- Drug-Induced Lipid Remodeling inMicroorganisms · 2021Article
- Gamma-glutamylcysteine synthetase and tryparedoxin 1 exert high control on the antioxidant system in Trypanosoma cruzi contributing to drug resistance and infectivity.Redox biology · 2019Article
- Increased thiol levels in antimony-resistant Leishmania infantum isolated from treatment-refractory visceral leishmaniasis in Brazil.Memorias do Instituto Oswaldo Cruz · 2018Article
- Imipramine alters the sterol profile in Leishmania amazonensis and increases its sensitivity to miconazole.Parasites & vectors · 2016Article
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3 authors at 3 institutions in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
backgroundVisceral leishmaniasis (VL), also called Kala Azar (KA) or black fever in India, claims around 20,000 lives every year. Chemotherapy remains one of the most important tools in the control of VL. Current chemotherapy for Kala Azar in India relies on a rather limited arsenal of drugs including sodium antimony gluconate and amphotericin B in addition to the very expensive drug miltefosine. Pentavalent antimonials have been used for more than half a century in the therapy of leishmaniasis as it is relatively safe and inexpensive, however, the spread of resistance to this drug is forcing clinicians in India to abandon this treatment. Consequently, improvement of antimonial chemotherapy has become a major challenging area of study by leishmaniacs worldwide. The alarming emergence of resistance to the commonly used antleishmanial drug, sodium antimony gluconate, in India, has led us to elucidate the resistance mechanism(s) in clinical isolates. Studies on laboratory mutants have shown that resistance to antimonials is highly dependent on thiol levels. The parasite evades cytotoxic effects of antimonial therapy by enhanced efflux of drug upon conjugation with thiols, through overexpressed membrane proteins belonging to the superfamily of ABC transporters.
methodsWe have carried out functional studies to determine the activity of the efflux pumps in antimonial resistant clinical isolates collected from disease endemic areas in India and also carried out molecular characterization of thiol levels in these parasites.
resultsOverexpression of the gene coding for γ glutamylcysteine synthetase was observed in these resistant clinical isolates thereby establishing that thiols represent the key determinants of antimonial resistance. The SbIII/thiol conjugates can be sequestered by ABC transporter multidrug resistance protein A (MRPA) into intracellular organelles or can be directly pumped out by an uncharacterized transporter.
conclusionsOur studies investigating antimonial resistance in different L. donovani clinical isolates suggest that over functioning of MRP plays a role in generation of antimony resistance phenotype in some L. donovani clinical isolates.
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