ArticleParasitology research2015
Antileishmanial effect of mevastatin is due to interference with sterol metabolism.
Article in Parasitology research, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 23 citations in OpenAlex.
- Polyamine Metabolism for Drug Intervention in Trypanosomatids.Pathogens (Basel, Switzerland) · 2024Review
- Recent Advances in Chemotherapeutics for Leishmaniasis: Importance of the Cellular Biochemistry of the Parasite and Its Molecular Interaction with the Host.Pathogens (Basel, Switzerland) · 2023Review
- Fatty Acid Composition and Metabolism inInternational journal of molecular sciences · 2023Review
- Metabolic Pathways ofPharmaceutics · 2022Review
- Simvastatin Resistance ofMicroorganisms · 2022Article
- Microorganisms as a Potential Source of Molecules to Control Trypanosomatid Diseases.Molecules (Basel, Switzerland) · 2021Review
- Statins: a viable candidate for host-directed therapy against infectious diseases.Nature reviews. Immunology · 2019Review
- Repurposing as a strategy for the discovery of new anti-leishmanials: the-state-of-the-art.Parasitology · 2018Review
- Antileishmanial Activity of Ezetimibe: Inhibition of Sterol Biosynthesis, In Vitro Synergy with Azoles, and Efficacy in Experimental Cutaneous Leishmaniasis.Antimicrobial agents and chemotherapy · 2016Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Visceral leishmaniasis (VL) is one of the most severe forms of leishmaniasis which is fatal if left untreated. Sterol biosynthetic pathway in Leishmania is currently being explored for its therapeutic potential. In the present study, we have evaluated the antileishmanial efficacy of mevastatin, a known inhibitor of 3-hydroxy-3-methyl glutaryl-CoA reductase (HMGR) enzyme. Mevastatin inhibited Leishmania donovani promastigotes and intracellular amastigotes with an 50% inhibitory concentration (IC50) value of 23.8 ± 4.2 and 7.5 ± 1.1 μM, respectively, without exhibiting toxicity towards host cell line. Mevastatin also inhibited recombinant L. donovani HMGR (LdHMGR) enzyme activity with an IC50 value of 42.2 ± 3.0 μM. Kinetic analysis revealed that the inhibition of recombinant LdHMGR activity by mevastatin was competitive with HMG-CoA. Mevastatin-treated parasites exhibited 66% reduction in ergosterol levels with respect to untreated parasites. Incubation of mevastatin-treated L. donovani promastigotes with ergosterol resulted in revival of cell growth, whereas cholesterol supplementation failed to cause reversal in cell death. To further prove the specificity of mevastatin for HMGR enzyme, HMGR-overexpressing parasites were used which showed almost threefold resistance to mevastatin. It also induced morphological changes in the parasite accompanied by lipid body accumulation. Hence, antileishmanial effect of mevastatin was due to the inhibition of HMGR, which eventually leads to reduction in ergosterol levels and hence parasite death. The present study may have implications in the treatment of visceral form of leishmaniasis.
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