ArticlePLoS neglected tropical diseases2016
Trypanosoma brucei CYP51: Essentiality and Targeting Therapy in an Experimental Model.
Article in PLoS neglected tropical diseases, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 13 papers.
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13 citing papers in PubMed, 33 citations in OpenAlex.
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- Heme-deficient metabolism and impaired cellular differentiation as an evolutionary trade-off for human infectivity in Trypanosoma brucei gambiense.Nature communications · 2022Article
- Systematic identification of genes encoding cell surface and secreted proteins that are essential for in vitro growth and infection in Leishmania donovani.PLoS pathogens · 2022Article
- Double-stranded RNA targeting fungal ergosterol biosynthesis pathway controls Botrytis cinerea and postharvest grey mould.Plant biotechnology journal · 2022Article
- The Actigraphy Sleep Score: A New Biomarker for Diagnosis, Disease Staging, and Monitoring in Human African Trypanosomiasis.The American journal of tropical medicine and hygiene · 2020Article
- Insights into Ergosterol Peroxide's Trypanocidal Activity.Biomolecules · 2019Article
- CYP51 as drug targets for fungi and protozoan parasites: past, present and future.Parasitology · 2018Review
- Microbial Sterolomics as a Chemical Biology Tool.Molecules (Basel, Switzerland) · 2018Review
- Mutations in CFAP43 and CFAP44 cause male infertility and flagellum defects in Trypanosoma and human.Nature communications · 2018Article
- Discovery and Genetic Validation of Chemotherapeutic Targets for Chagas' Disease.Frontiers in cellular and infection microbiology · 2018Review
- The Presence or Absence of Intestinal Microbiota Affects Lipid Deposition and Related Genes Expression in Zebrafish (Frontiers in microbiology · 2018Article
- Article
- Correction: Trypanosoma brucei CYP51: Essentiality and Targeting Therapy in an Experimental Model.PLoS neglected tropical diseases · 2017Article
Corrections and comments
- Erratum issued
Authors and funding
9 authors at 5 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Trypanosoma brucei gambiense is the main causative agent of Human African Trypanosomiasis (HAT), also known as sleeping sickness. Because of limited alternatives and treatment toxicities, new therapeutic options are urgently needed for patients with HAT. Sterol 14alpha-demethylase (CYP51) is a potential drug target but its essentiality has not been determined in T. brucei. We used a tetracycline-inducible RNAi system to assess the essentiality of CYP51 in T. brucei bloodstream form (BSF) cells and we evaluated the effect of posaconazole, a well-tolerated triazole drug, within a panel of virulent strains in vitro and in a murine model. Expression of CYP51 in several T. brucei cell lines was demonstrated by western blot and its essentiality was demonstrated by RNA interference (CYP51RNAi) in vitro. Following reduction of TbCYP51 expression by RNAi, cell growth was reduced and eventually stopped compared to WT or non-induced cells, showing the requirement of CYP51 in T. brucei. These phenotypes were rescued by addition of ergosterol. Additionally, CYP51RNAi induction caused morphological defects with multiflagellated cells (p<0.05), suggesting cytokinesis dysfunction. The survival of CYP51RNAi Doxycycline-treated mice (p = 0.053) and of CYP51RNAi 5-day pre-induced Doxycycline-treated mice (p = 0.008) were improved compared to WT showing a CYP51 RNAi effect on trypanosomal virulence in mice. The posaconazole concentrations that inhibited parasite growth by 50% (IC50) were 8.5, 2.7, 1.6 and 0.12 μM for T. b. brucei 427 90-13, T. b. brucei Antat 1.1, T. b. gambiense Feo (Feo/ITMAP/1893) and T. b. gambiense Biyamina (MHOM/SD/82), respectively. During infection with these last three virulent strains, posaconazole-eflornithine and nifurtimox-eflornithine combinations showed similar improvement in mice survival (p≤0.001). Our results provide support for a CYP51 targeting based treatment in HAT. Thus posaconazole used in combination may represent a therapeutic alternative for trypanosomiasis.
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