ArticlePLoS pathogens2024
Sterol 14-alpha demethylase (CYP51) activity in Leishmania donovani is likely dependent upon cytochrome P450 reductase 1.
Article in PLoS pathogens, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers, 1 of them a synthesis that pooled it.
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Who cites it
11 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Efficacy and safety of different drugs for the treatment of leishmaniasis: a systematic review and network meta-analysis.Frontiers in cellular and infection microbiology · 2025Pooled it
- Visceral leishmaniasis: an integrated review of resistance mechanisms, host immunometabolism, and next generation therapeutics.Inflammopharmacology · 2026Review
- Towards precision antileishmanial drug discovery: Integrating multi-omics, functional genomics, artificial intelligence and host-directed therapeutics.Molecular biology reports · 2026Review
- Role of ergosterol biosynthesis in growth, drug sensitivity, and host colonization of honey bee trypanosomatid parasite,FEMS microbes · 2026Article
- Review
- Insights on genomic profiles of drug resistance and virulence in a cohort of Leishmania infantum isolates from the Mediterranean area.Parasites & vectors · 2025Article
- Reconstitution of Human Cytochrome P450 Activity using aACS synthetic biology · 2025Article
- C14DM Ablation Leads to Reduced Tolerance to Plasma Membrane Stress and Increased Drug Sensitivity inInternational journal of molecular sciences · 2025Article
- Antitrypanosomal quinazolines targeting lysyl-tRNA synthetase show partial efficacy in a mouse model of acute Chagas disease.Science translational medicine · 2025Article
- 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
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10 authors.
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Abstract
Liposomal amphotericin B is an important frontline drug for the treatment of visceral leishmaniasis, a neglected disease of poverty. The mechanism of action of amphotericin B (AmB) is thought to involve interaction with ergosterol and other ergostane sterols, resulting in disruption of the integrity and key functions of the plasma membrane. Emergence of clinically refractory isolates of Leishmania donovani and L. infantum is an ongoing issue and knowledge of potential resistance mechanisms can help to alleviate this problem. Here we report the characterisation of four independently selected L. donovani clones that are resistant to AmB. Whole genome sequencing revealed that in three of the moderately resistant clones, resistance was due solely to the deletion of a gene encoding C24-sterol methyltransferase (SMT1). The fourth, hyper-resistant resistant clone (>60-fold) was found to have a 24 bp deletion in both alleles of a gene encoding a putative cytochrome P450 reductase (P450R1). Metabolic profiling indicated these parasites were virtually devoid of ergosterol (0.2% versus 18% of total sterols in wild-type) and had a marked accumulation of 14-methylfecosterol (75% versus 0.1% of total sterols in wild-type) and other 14-alpha methylcholestanes. These are substrates for sterol 14-alpha demethylase (CYP51) suggesting that this enzyme may be a bona fide P450R specifically involved in electron transfer from NADPH to CYP51 during catalysis. Deletion of P450R1 in wild-type cells phenocopied the metabolic changes observed in our AmB hyper-resistant clone as well as in CYP51 nulls. Likewise, addition of a wild type P450R1 gene restored sterol profiles to wild type. Our studies indicate that P450R1 is essential for L. donovani amastigote viability, thus loss of this gene is unlikely to be a driver of clinical resistance. Nevertheless, investigating the mechanisms underpinning AmB resistance in these cells provided insights that refine our understanding of the L. donovani sterol biosynthetic pathway.
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