ArticlePLoS neglected tropical diseases2019
Genomic instability at the locus of sterol C24-methyltransferase promotes amphotericin B resistance in Leishmania parasites.
Article in PLoS neglected tropical diseases, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 60 citations in OpenAlex.
- Microneedle-based injection of Fungizone/Amphotericin B: an effective treatment for American cutaneous leishmaniasis in mice.Drug delivery · 2026Article
- Canalesolide A, a Structurally Unique Polyhydroxy Macrolide from the Marine Cyanobacterium Okeania sp. with Potent Antitrypanosomal Activity.Journal of the American Chemical Society · 2026Article
- Review on macrophage polarization during visceral leishmaniasis and impact of glycoprotein.Glycoconjugate journal · 2026Review
- Direct sequencing of Leishmania donovani from patients in Garissa County, Northern Kenya, reveals a newly emerging intra-specific hybrid genotype.PLoS neglected tropical diseases · 2026Article
- Role of ergosterol biosynthesis in growth, drug sensitivity, and host colonization of honey bee trypanosomatid parasite,FEMS microbes · 2026Article
- Genomic characterization of Leishmania (V.) braziliensis associated with antimony therapeutic failure and variable in vitro tolerance to amphotericin B.Scientific reports · 2025Article
- Genome analyses of amphotericin B-susceptible and -resistant strains ofCurrent research in parasitology & vector-borne diseases · 2025Article
- Unravelling drug resistance in leishmaniasis: genomic adaptations and emerging therapies.Frontiers in molecular biosciences · 2025Review
- Genome alteration of Leishmania orientalis under Amphotericin B inhibiting conditions.PLoS neglected tropical diseases · 2024Article
- Possibility of re-purposing antifungal drugs posaconazole & isavuconazole against promastigote form of Leishmania major.The Indian journal of medical research · 2024Article
- Molecular Mechanisms of Drug Resistance inPathogens (Basel, Switzerland) · 2024Review
- Article
- Sterol 14-alpha demethylase (CYP51) activity in Leishmania donovani is likely dependent upon cytochrome P450 reductase 1.PLoS pathogens · 2024Article
- Amphotericin B resistance in Leishmania amazonensis: In vitro and in vivo characterization of a Brazilian clinical isolate.PLoS neglected tropical diseases · 2024Article
- Genomic Insight of Leishmania Parasite: In-Depth Review of Drug Resistance Mechanisms and Genetic Mutations.ACS omega · 2024Review
- In vitro susceptibility to miltefosine of amphotericin B-resistant Leishmania (Mundinia) martiniquensis.Parasitology research · 2023Article
- Amphotericin B resistance correlates with increased fitnessFrontiers in microbiology · 2023Article
- Amphotericin B resistance in Leishmania mexicana: Alterations to sterol metabolism and oxidative stress response.PLoS neglected tropical diseases · 2022Article
- New Glycosylated Polyene Macrolides: Refining the Ore from Genome Mining.Antibiotics (Basel, Switzerland) · 2022Review
- Simvastatin Resistance ofMicroorganisms · 2022Article
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Authors and funding
7 authors at 4 institutions in 2 countries.
Funding
Abstract
Amphotericin B is an increasingly important tool in efforts to reduce the global disease burden posed by Leishmania parasites. With few other chemotherapeutic options available for the treatment of leishmaniasis, the potential for emergent resistance to this drug is a considerable threat. Here we characterised four novel amphotericin B-resistant Leishmania mexicana lines. All lines exhibited altered sterol biosynthesis, and hypersensitivity to pentamidine. Whole genome sequencing demonstrated resistance-associated mutation of the sterol biosynthesis gene sterol C5-desaturase in one line. However, in three out of four lines, RNA-seq revealed loss of expression of sterol C24-methyltransferase (SMT) responsible for drug resistance and altered sterol biosynthesis. Additional loss of the miltefosine transporter was associated with one of those lines. SMT is encoded by two tandem gene copies, which we found to have very different expression levels. In all cases, reduced overall expression was associated with loss of the 3' untranslated region of the dominant gene copy, resulting from structural variations at this locus. Local regions of sequence homology, between the gene copies themselves, and also due to the presence of SIDER1 retrotransposon elements that promote multi-gene amplification, correlate to these structural variations. Moreover, in at least one case loss of SMT expression was not associated with loss of virulence in primary macrophages or in vivo. Whilst such repeat sequence-mediated instability is known in Leishmania genomes, its presence associated with resistance to a major antileishmanial drug, with no evidence of associated fitness costs, is a significant concern.
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