ArticleNucleic acids research2022
Oligo targeting for profiling drug resistance mutations in the parasitic trypanosomatids.
Article in Nucleic acids research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 23 citations in OpenAlex.
- Identification of New Anti-Trypanosoma brucei Leads: An Integrated CRK12-Guided Virtual Screen With Experimental Validation.Chemical biology & drug design · 2026Article
- Late-Stage Functionalization via Thianthrenation: A Reaction Enabling Rapid Preparation of Drug Beads for Chemical Pulldown.Journal of medicinal chemistry · 2026Article
- Beyond resistance: Emerging methods to dissect drug responses in Leishmania.PLoS pathogens · 2026Review
- Genetic origins and proteomic consequences of kinetoplast loss in trypanosomes.PLoS pathogens · 2026Article
- Acoziborole resistance associated mutations in Trypanosoma brucei CPSF3.PLoS pathogens · 2026Article
- Decoding efficacy and resistance space at a drug binding site.Nature communications · 2026Article
- CRISPR-Cas9 precision editing of kinetochore protein phosphosite codons inFrontiers in cellular and infection microbiology · 2026Article
- A CRISPR-based diagnostic tool to survey drug resistance in human African trypanosomiasis.Antimicrobial agents and chemotherapy · 2025Article
- Article
- Antitrypanosomal quinazolines targeting lysyl-tRNA synthetase show partial efficacy in a mouse model of acute Chagas disease.Science translational medicine · 2025Article
- Precision-edited histone tails disrupt polycistronic gene expression controls in trypanosomes.Nature communications · 2025Article
- Next generation genetic screens in kinetoplastids.Nucleic acids research · 2025Review
- Discovery of Novel CRK12 Inhibitors for the Treatment of Human African Trypanosomiasis: An Integrated Computational and Experimental Approach.Pharmaceuticals (Basel, Switzerland) · 2025Article
- Deep mutational scanning of the RNase III-like domain inFrontiers in cellular and infection microbiology · 2024Article
- Pathogenicity and virulence of African trypanosomes: From laboratory models to clinically relevant hosts.Virulence · 2023Review
- Targeting trypanosomes: how chemogenomics and artificial intelligence can guide drug discovery.Biochemical Society transactions · 2023Review
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
Abstract
Trypanosomatids cause the neglected tropical diseases, sleeping sickness, Chagas disease and the leishmaniases. Studies on these lethal parasites would be further facilitated by new and improved genetic technologies. Scalable precision editing methods, for example, could be used to improve our understanding of potential mutations associated with drug resistance, a current priority given that several new anti-trypanosomal drugs, with known targets, are currently in clinical development. We report the development of a simple oligo targeting method for rapid and precise editing of priority drug targets in otherwise wild type trypanosomatids. In Trypanosoma brucei, approx. 50-b single-stranded oligodeoxynucleotides were optimal, multiple base edits could be incorporated, and editing efficiency was substantially increased when mismatch repair was suppressed. Resistance-associated edits were introduced in T. brucei cyclin dependent kinase 12 (CRK12, L482F) or cleavage and polyadenylation specificity factor 3 (N232H), in the Trypanosoma cruzi proteasome β5 subunit (G208S), or in Leishmania donovani CRK12 (G572D). We further implemented oligo targeting for site saturation mutagenesis, targeting codon G492 in T. brucei CRK12. This approach, combined with amplicon sequencing for codon variant scoring, revealed fourteen resistance conferring G492 edits encoding six distinct amino acids. The outputs confirm on-target drug activity, reveal a variety of resistance-associated mutations, and facilitate rapid assessment of potential impacts on drug efficacy.
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