Yeast as a tool to uncover the cellular targets of drugs

Sturgeon, Christopher M.; Kemmer, Danielle; Anderson, Hilary; Roberge, Michel

doi:10.1002/biot.200500039

Cited by 45 publications

(50 citation statements)

References 42 publications

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“…While 6-NDA showed similar potency as amphotericin B against C. albicans (IC 50 of 0.28 g/ml for both), its IC 50 against A. fumigatus (0.34 g/ml) was approximately 2.5-fold lower than that of amphotericin B (0.86 g/ml). To determine the cellular effects of 6-NDA in fungal cells, we made use of S. cerevisiae, a well-established model organism that has been successfully utilized in identifying the molecular pathways targeted by antifungal and therapeutic compounds (34,47). A transcriptional profiling study was conducted in S. cerevisiae cells (strain S288C) that were exposed for a period of approximately one doubling time (ϳ4 h) to 2.2 g/ml of 6-NDA, a concentration resulting in 50% growth inhibition.…”

Section: Resultsmentioning

confidence: 99%

A Potent Plant-Derived Antifungal Acetylenic Acid Mediates Its Activity by Interfering with Fatty Acid Homeostasis

Tripathi

Feng

et al. 2012

Antimicrob Agents Chemother

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c 6-Nonadecynoic acid (6-NDA), a plant-derived acetylenic acid, exhibits strong inhibitory activity against the human fungal pathogens Candida albicans, Aspergillus fumigatus, and Trichophyton mentagrophytes. In the present study, transcriptional profiling coupled with mutant and biochemical analyses were conducted using the model yeast Saccharomyces cerevisiae to investigate its mechanism of action. 6-NDA elicited a transcriptome response indicative of fatty acid stress, altering the expression of genes that are required for yeast growth in the presence of oleate. Mutants of S. cerevisiae lacking transcription factors that regulate fatty acid ␤-oxidation showed increased sensitivity to 6-NDA. Fatty acid profile analysis indicated that 6-NDA inhibited the formation of fatty acids longer than 14 carbons in length. In addition, the growth inhibitory effect of 6-NDA was rescued in the presence of exogenously supplied oleate. To investigate the response of a pathogenic fungal species to 6-NDA, transcriptional profiling and biochemical analyses were also conducted in C. albicans. The transcriptional response and fatty acid profile of C. albicans were comparable to those obtained in S. cerevisiae, and the rescue of growth inhibition with exogenous oleate was also observed in C. albicans. In a fluconazole-resistant clinical isolate of C. albicans, a fungicidal effect was produced when fluconazole was combined with 6-NDA. In hyphal growth assays, 6-NDA inhibited the formation of long hyphal filaments in C. albicans. Collectively, our results indicate that the antifungal activity of 6-NDA is mediated by a disruption in fatty acid homeostasis and that 6-NDA has potential utility in the treatment of superficial Candida infections.

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Section: Resultsmentioning

confidence: 99%

A Potent Plant-Derived Antifungal Acetylenic Acid Mediates Its Activity by Interfering with Fatty Acid Homeostasis

Tripathi

Feng

et al. 2012

Antimicrob Agents Chemother

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“…Unfortunately, the protein targets of many compounds are still, in large part, unknown and compound selection remains a challenge. Although several yeast genomics-based strategies have been developed to identify drug targets (Sturgeon et al 2006), each has certain limitations. For example, haploinsufficiency profiling (HIP) represents an assay with the potential to reveal drug targets (Giaever et al 1999(Giaever et al , 2002(Giaever et al , 2004Baetz et al 2004;Lum et al 2004;Doostzadeh et al 2007) but it can fail to identify drug targets if the reduction in gene dose is insufficient.…”

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confidence: 99%

Precise Gene-Dose Alleles for Chemical Genetics

et al. 2009

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Modulating gene dose is an effective way to alter protein levels and modify phenotypes to understand gene function. In addition, combining gene-dose alleles with chemical perturbation can provide insight into drug-gene interactions. Here, we present a strategy that combines diverse loss-of-function alleles to systematically modulate gene dose in Saccharomyces cerevisiae. The generated gene dosage allele set expands the genetic toolkit for uncovering novel phenotypes.

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“…Screening the yeast "disruptome" has proved to be a useful high-throughput functional genomic tool to identify genes involved in responsiveness to drugs (27,44) as well as other phenotypes. Although mutations in genes encoding components involved in the translocation process are plausible candidates to render cells resistant or sensitive to sordarin, it is likely that other mechanisms participate in the response.…”

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confidence: 99%

A Chemical Genomic Screen in Saccharomyces cerevisiae Reveals a Role for Diphthamidation of Translation Elongation Factor 2 in Inhibition of Protein Synthesis by Sordarin

Botet

Rodríguez-Mateos

Ballesta

et al. 2008

Antimicrob Agents Chemother

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Sordarin and its derivatives are antifungal compounds of potential clinical interest. Despite the highly conserved nature of the fungal and mammalian protein synthesis machineries, sordarin is a selective inhibitor of protein synthesis in fungal organisms. In cells sensitive to sordarin, its mode of action is through preventing the release of translation elongation factor 2 (eEF2) during the translocation step, thus blocking protein synthesis. To further investigate the cellular components required for the effects of sordarin in fungal cells, we have used the haploid deletion collection of Saccharomyces cerevisiae to systematically identify genes whose deletion confers sensitivity or resistance to the compound. Our results indicate that genes in a number of cellular pathways previously unknown to play a role in sordarin response are involved in its growth effects on fungal cells and reveal a specific requirement for the diphthamidation pathway of cells in causing eEF2 to be sensitive to the effects of sordarin on protein synthesis. Our results underscore the importance of the powerful genomic tools developed in yeast (Saccharomyces cerevisiae) to more comprehensively understanding the cellular mechanisms involved in the response to therapeutic agents.

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Yeast as a tool to uncover the cellular targets of drugs

Cited by 45 publications

References 42 publications

A Potent Plant-Derived Antifungal Acetylenic Acid Mediates Its Activity by Interfering with Fatty Acid Homeostasis

A Potent Plant-Derived Antifungal Acetylenic Acid Mediates Its Activity by Interfering with Fatty Acid Homeostasis

Precise Gene-Dose Alleles for Chemical Genetics

A Chemical Genomic Screen in Saccharomyces cerevisiae Reveals a Role for Diphthamidation of Translation Elongation Factor 2 in Inhibition of Protein Synthesis by Sordarin

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