ArticlePLoS pathogens2014
Sterol biosynthesis is required for heat resistance but not extracellular survival in leishmania.
Article in PLoS pathogens, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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48 citing papers in PubMed, 74 citations in OpenAlex.
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- C14DM Ablation Leads to Reduced Tolerance to Plasma Membrane Stress and Increased Drug Sensitivity inInternational journal of molecular sciences · 2025Article
- N-substituted-4-(pyridin-4-ylalkyl)piperazine-1-carboxamides and related compounds as Leishmania CYP51 and CYP5122A1 inhibitors.Bioorganic & medicinal chemistry · 2024Article
- Possibility of re-purposing antifungal drugs posaconazole & isavuconazole against promastigote form of Leishmania major.The Indian journal of medical research · 2024Article
- CYP5122A1 encodes an essential sterol C4-methyl oxidase in Leishmania donovani and determines the antileishmanial activity of antifungal azoles.Nature communications · 2024Article
- Molecular Characterization of Sterol C4-Methyl Oxidase inInternational journal of molecular sciences · 2024Article
- Sterol 14-alpha demethylase (CYP51) activity in Leishmania donovani is likely dependent upon cytochrome P450 reductase 1.PLoS pathogens · 2024Article
- In Vitro and In Silico Evaluations of the Antileishmanial Activities of New Benzimidazole-Triazole Derivatives.Veterinary sciences · 2023Article
- Ethanolaminephosphate cytidylyltransferase is essential for survival, lipid homeostasis and stress tolerance in Leishmania major.PLoS pathogens · 2023Article
- The Antileishmanial Activity of Eugenol Associated with Lipid Storage Reduction Rather Than Membrane Properties Alterations.Molecules (Basel, Switzerland) · 2023Article
- Low-THz Vibrations of Biological Membranes.Membranes · 2023Article
- Ethanolaminephosphate cytidyltransferase is essential for survival, lipid homeostasis and stress tolerance inbioRxiv : the preprint server for biology · 2023Article
- Systems biology of autophagy in leishmanial infection and its diverse role in precision medicine.Frontiers in molecular biosciences · 2023Review
- The Golgi-localized sphingosine-1-phosphate phosphatase is indispensable for Leishmania major.Scientific reports · 2022Article
- Amphotericin B resistance in Leishmania mexicana: Alterations to sterol metabolism and oxidative stress response.PLoS neglected tropical diseases · 2022Article
- Repurposing Lansoprazole and Posaconazole to treat leishmaniasis: Integration of in vitro testing, pharmacological corroboration, and mechanisms of action.Journal of food and drug analysis · 2022Article
- Endogenous Sterol Synthesis Is Dispensable forFrontiers in microbiology · 2022Article
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5 authors at 2 institutions in 1 country.
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Abstract
Sterol biosynthesis is a crucial pathway in eukaryotes leading to the production of cholesterol in animals and various C24-alkyl sterols (ergostane-based sterols) in fungi, plants, and trypanosomatid protozoa. Sterols are important membrane components and precursors for the synthesis of powerful bioactive molecules, including steroid hormones in mammals. Their functions in pathogenic protozoa are not well characterized, which limits the development of sterol synthesis inhibitors as drugs. Here we investigated the role of sterol C14α-demethylase (C14DM) in Leishmania parasites. C14DM is a cytochrome P450 enzyme and the primary target of azole drugs. In Leishmania, genetic or chemical inactivation of C14DM led to a complete loss of ergostane-based sterols and accumulation of 14-methylated sterols. Despite the drastic change in lipid composition, C14DM-null mutants (c14dm(-)) were surprisingly viable and replicative in culture. They did exhibit remarkable defects including increased membrane fluidity, failure to maintain detergent resistant membrane fraction, and hypersensitivity to heat stress. These c14dm(-) mutants showed severely reduced virulence in mice but were highly resistant to itraconazole and amphotericin B, two drugs targeting sterol synthesis. Our findings suggest that the accumulation of toxic sterol intermediates in c14dm(-) causes strong membrane perturbation and significant vulnerability to stress. The new knowledge may help improve the efficacy of current drugs against pathogenic protozoa by exploiting the fitness loss associated with drug resistance.
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