ArticleMolecular bioSystems2014
Confirmation of the cellular targets of benomyl and rapamycin using next-generation sequencing of resistant mutants in S. cerevisiae.
Article in Molecular bioSystems, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 20 citations in OpenAlex.
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- Experimental evolution of Saccharomyces cerevisiae for caffeine tolerance alters multidrug resistance and target of rapamycin signaling pathways.G3 (Bethesda, Md.) · 2024Article
- Experimental evolution ofbioRxiv : the preprint server for biology · 2024Article
- Robust microtubule dynamics facilitate low-tension kinetochore detachment in metaphase.The Journal of cell biology · 2023Article
- Chemical reactivity, molecular electrostatic potential and in-silico analysis on benzimidazole fungicide benomyl.Heliyon · 2022Article
- Next-Generation Sequencing Applications for the Study of Fungal Pathogens.Microorganisms · 2022Review
- Adaptive laboratory evolution in S. cerevisiae highlights role of transcription factors in fungal xenobiotic resistance.Communications biology · 2022Article
- Using Budding Yeast to Identify Molecules That Block Cancer Cell 'Mitotic Slippage' Only in the Presence of Mitotic Poisons.International journal of molecular sciences · 2021Review
- From Yeast to Humans: Leveraging New Approaches in Yeast to Accelerate Discovery of Therapeutic Targets for Synucleinopathies.Methods in molecular biology (Clifton, N.J.) · 2019Article
- Computer-Aided Drug Discovery in Plant Pathology.The plant pathology journal · 2017Review
- Genomic sequencing-based mutational enrichment analysis identifies motility genes in a genetically intractable gut microbe.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Reverse Chemical Genetics: Comprehensive Fitness Profiling Reveals the Spectrum of Drug Target Interactions.PLoS genetics · 2016Article
- Comparative chemical genomics reveal that the spiroindolone antimalarial KAE609 (Cipargamin) is a P-type ATPase inhibitor.Scientific reports · 2016Article
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 1 country.
Funding
Abstract
Investigating the mechanisms of action (MOAs) of bioactive compounds and the deconvolution of their cellular targets is an important and challenging undertaking. Drug resistance in model organisms such as S. cerevisiae has long been a means for discovering drug targets and MOAs. Strains are selected for resistance to a drug of interest, and the resistance mutations can often be mapped to the drug's molecular target using classical genetic techniques. Here we demonstrate the use of next generation sequencing (NGS) to identify mutations that confer resistance to two well-characterized drugs, benomyl and rapamycin. Applying NGS to pools of drug-resistant mutants, we develop a simple system for ranking single nucleotide polymorphisms (SNPs) based on their prevalence in the pool, and for ranking genes based on the number of SNPs that they contain. We clearly identified the known targets of benomyl (TUB2) and rapamycin (FPR1) as the highest-ranking genes under this system. The highest-ranking SNPs corresponded to specific amino acid changes that are known to confer resistance to these drugs. We also found that by screening in a pdr1Δ null background strain that lacks a transcription factor regulating the expression of drug efflux pumps, and by pre-screening mutants in a panel of unrelated anti-fungal agents, we were able to mitigate against the selection of multi-drug resistance (MDR) mutants. We call our approach "Mutagenesis to Uncover Targets by deep Sequencing", or "MUTseq", and show through this proof-of-concept study its potential utility in characterizing MOAs and targets of novel compounds.
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