ArticleProceedings of the National Academy of Sciences of the United States of America2016
Cos-Seq for high-throughput identification of drug target and resistance mechanisms in the protozoan parasite Leishmania.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
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57 citing papers in PubMed, 85 citations in OpenAlex.
- New thinking for the next generation of antimalarials.EMBO molecular medicine · 2026Review
- Miltefosine and emerging Leishmania (Mundinia) in Southeast Asia: Molecular insights, therapeutic challenges, and future strategic implementation.PLoS neglected tropical diseases · 2026Review
- Beyond resistance: Emerging methods to dissect drug responses in Leishmania.PLoS pathogens · 2026Review
- Limonene and carvacrol combined with drugs that inhibit ergosterol synthesis are potent against Leishmania major.Naunyn-Schmiedeberg's archives of pharmacology · 2026Article
- CRISPR-Cas13b mediated gene knockdowns in Leishmania infantum.International journal for parasitology. Drugs and drug resistance · 2025Article
- Next generation genetic screens in kinetoplastids.Nucleic acids research · 2025Review
- Genomic characterization of Leishmania (V.) braziliensis associated with antimony therapeutic failure and variable in vitro tolerance to amphotericin B.Scientific reports · 2025Article
- Molecular Mechanisms of Drug Resistance inPathogens (Basel, Switzerland) · 2024Review
- Article
- Potential selection of antimony and methotrexate cross-resistance in Leishmania infantum circulating strains.PLoS neglected tropical diseases · 2024Article
- Antimony resistance and gene expression inParasitology · 2024Review
- Synthetic biology for combating leishmaniasis.Frontiers in microbiology · 2024Article
- Drug Discovery for Cutaneous Leishmaniasis: A Review of Developments in the Past 15 Years.Microorganisms · 2023Review
- Chemical genetic approaches for the discovery of bacterial cell wall inhibitors.RSC medicinal chemistry · 2023Review
- Delving in folate metabolism in the parasite Leishmania major through a chemogenomic screen and methotrexate selection.PLoS neglected tropical diseases · 2023Article
- Recent Advances in Chemotherapeutics for Leishmaniasis: Importance of the Cellular Biochemistry of the Parasite and Its Molecular Interaction with the Host.Pathogens (Basel, Switzerland) · 2023Review
- The critical role of mode of action studies in kinetoplastid drug discovery.Frontiers in drug discovery · 2023Article
- Targeting trypanosomes: how chemogenomics and artificial intelligence can guide drug discovery.Biochemical Society transactions · 2023Review
- Immunosuppressants alter the immune response associated with GlucantimeFrontiers in immunology · 2023Article
- The paradigm of intracellular parasite survival and drug resistance in leishmanial parasite through genome plasticity and epigenetics: Perception and future perspective.Frontiers in cellular and infection microbiology · 2023Review
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Innovative strategies are needed to accelerate the identification of antimicrobial drug targets and resistance mechanisms. Here we develop a sensitive method, which we term Cosmid Sequencing (or "Cos-Seq"), based on functional cloning coupled to next-generation sequencing. Cos-Seq identified >60 loci in the Leishmania genome that were enriched via drug selection with methotrexate and five major antileishmanials (antimony, miltefosine, paromomycin, amphotericin B, and pentamidine). Functional validation highlighted both known and previously unidentified drug targets and resistance genes, including novel roles for phosphatases in resistance to methotrexate and antimony, for ergosterol and phospholipid metabolism genes in resistance to miltefosine, and for hypothetical proteins in resistance to paromomycin, amphothericin B, and pentamidine. Several genes/loci were also found to confer resistance to two or more antileishmanials. This screening method will expedite the discovery of drug targets and resistance mechanisms and is easily adaptable to other microorganisms.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.