ArticleInternational journal for parasitology. Drugs and drug resistance2018
High-throughput Cos-Seq screen with intracellular Leishmania infantum for the discovery of novel drug-resistance mechanisms.
Article in International journal for parasitology. Drugs and drug resistance, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed.
- CRISPR-Cas13b mediated gene knockdowns in Leishmania infantum.International journal for parasitology. Drugs and drug resistance · 2025Article
- Genetic Manipulation Tools in Leishmania: From CRISPR/Cas9 to Vaccine Strategies for Disease Control.Acta parasitologica · 2025Review
- High-throughput screening identifies novel chemical scaffolds targeting Leishmania donovani parasites.World journal of microbiology & biotechnology · 2025Article
- Article
- Recent Advances in CRISPR/Cas9-Mediated Genome Editing in Leishmania Strains.Acta parasitologica · 2024Review
- Potential selection of antimony and methotrexate cross-resistance in Leishmania infantum circulating strains.PLoS neglected tropical diseases · 2024Article
- Identification of potential novel proteomic markers ofFrontiers in cellular and infection microbiology · 2024Article
- Antimony resistance and gene expression inParasitology · 2024Review
- Synthetic biology for combating leishmaniasis.Frontiers in microbiology · 2024Article
- Chemical genetic approaches for the discovery of bacterial cell wall inhibitors.RSC medicinal chemistry · 2023Review
- Targeting trypanosomes: how chemogenomics and artificial intelligence can guide drug discovery.Biochemical Society transactions · 2023Review
- Mutation Characteristics and Phylogenetic Analysis of FiveAnimals : an open access journal from MDPI · 2022Article
- Laboratory Selection of Trypanosomatid Pathogens for Drug Resistance.Pharmaceuticals (Basel, Switzerland) · 2022Review
- Impact of Genetic Diversity and Genome Plasticity ofFrontiers in cellular and infection microbiology · 2022Review
- Exploring direct and indirect targets of current antileishmanial drugs using a novel thermal proteomics profiling approach.Frontiers in cellular and infection microbiology · 2022Article
- Decreased glutamate transport in acivicin resistant Leishmania tarentolae.PLoS neglected tropical diseases · 2021Article
- Three different mutations in the DNA topoisomerase 1B in Leishmania infantum contribute to resistance to antitumor drug topotecan.Parasites & vectors · 2021Article
- Article
- MRPA-independent mechanisms of antimony resistance in Leishmania infantum.International journal for parasitology. Drugs and drug resistance · 2020Article
- Unravelling the proteomic signature of extracellular vesicles released by drug-resistant Leishmania infantum parasites.PLoS neglected tropical diseases · 2020Article
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7 authors.
Funding
Abstract
Increasing drug resistance towards first line antimony-derived compounds has forced the introduction of novel therapies in leishmaniasis endemic areas including amphotericin B and miltefosine. However, their use is threatened by the emergence and spread of drug-resistant strains. In order to discover stage-dependent resistance genes, we have adapted the Cos-Seq approach through the introduction of macrophage infections in the pipeline. A L. infantum intracellular amastigote population complemented with a L. infantum cosmid library was submitted to increasing concentrations of miltefosine, amphotericin B and pentavalent antimonials in experimental infections of THP-1 cells. For each step of selection, amastigotes were extracted and cosmids were isolated and submitted to next-generation sequencing, followed by subsequent gene-enrichment analyses. Cos-Seq screen in amastigotes revealed four highly enriched loci for antimony, five for miltefosine and one for amphotericin B. Of these, a total of seven cosmids were recovered and tested for resistance in both promastigotes and amastigotes. Candidate genes within the pinpointed genomic regions were validated using single gene overexpression in wild-type parasites and/or gene disruption by means of a CRISPR-Cas9-based approach. This led to the identification and validation of a stage-independent antimony-resistance gene (LinJ.06.1010) coding for a putative leucine rich repeat protein and a novel amastigote-specific miltefosine-resistance gene (LinJ.32.0050) coding for a member of the SEC13 family of WD-repeat proteins. This study further reinforces the power of Cos-Seq approach to discover novel drug-resistance genes, some of which are life-stages specific.
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