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| Status |
Public on Feb 16, 2018 |
| Title |
Gene expression response to eupolauridine-9591 (E9591) and liriodenine methiodide (LMT) in Saccharomyces cerevisiae |
| Platform organisms |
Schizosaccharomyces pombe; Saccharomyces cerevisiae |
| Sample organism |
Saccharomyces cerevisiae |
| Experiment type |
Expression profiling by array
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| Summary |
Eupolauridine and liriodenine are plant-derived aporphinoid alkaloids that exhibit potent inhibitory activity against the opportunistic fungal pathogens Candida albicans and Cryptococcus neoformans. However, the molecular mechanism of this antifungal activity is unknown. In this study, we show that eupolauridine 9591 (E9591), a synthetic analog of eupolauridine, and liriodenine methiodide (LMT), a methiodide salt of liriodenine, mediate their antifungal activities by disrupting mitochondrial iron-sulfur (Fe-S) cluster synthesis. Several lines of evidence supported this conclusion. First, both E9591 and LMT elicited a transcriptional response indicative of iron imbalance, causing the induction of genes that are required for iron uptake and for the maintenance of cellular iron homeostasis. Second, a genome-wide fitness profile analysis showed that yeast mutants with deletions in iron homeostasis–related genes were hypersensitive to E9591 and LMT. Third, treatment of wild-type yeast cells with E9591 or LMT generated cellular defects that mimicked deficiencies in mitochondrial Fe-S cluster synthesis, including an increase in mitochondrial iron levels, a decrease in the activities of Fe-S cluster enzymes, a decrease in respiratory function, and an increase in oxidative stress. Collectively, our results demonstrate that E9591 and LMT perturb mitochondrial Fe-S cluster biosynthesis; thus, these two compounds target a cellular pathway that is distinct from the pathways commonly targeted by clinically used antifungal drugs. Therefore, the identification of this pathway as a target for antifungal compounds has potential applications in the development of new antifungal therapies.
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| Overall design |
Cultures of S. cerevisiae strain S288C were started at OD600 of 0.1, allowed to grow to OD600 of 0.2, then treated with eupolauridine-9591 (E9591), liriodinine methiodide (LMT), 1,10-phenanthroline (PHEN), or 2,2'-bipyridyl (BIPR) at their respective IC50 concentrations (0.053 uM, 2.6 uM, 6.2 uM, and 65.9 uM respectively). Control cultures were simultaneously treated with 0.25% DMSO. PHEN and BIPR served as reference compounds for iron deficiency response. When OD600 of 0.5 was reached (~4 h), cells were harvested and frozen. For the long-term exposure experiment, all experimental conditions were the same except cells were exposed to compound treatments for 4.5 doublings (~ 15 h). In all experiments, three biological replicate cultures were grown for each treatment, and RNA from each replicate was hybridized to an independent array.
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| Contributor(s) |
Agarwal AK |
| Citation(s) |
28821607 |
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| Submission date |
Jul 21, 2017 |
| Last update date |
Jul 25, 2021 |
| Contact name |
Ameeta Agarwal |
| E-mail(s) |
aagarwal@olemiss.edu
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| Phone |
662-915-1218
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| Organization name |
University of Mississippi
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| Department |
National Center for Natural Products Research
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| Street address |
NCNPR, Room 2049
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| City |
University |
| State/province |
MS |
| ZIP/Postal code |
38677 |
| Country |
USA |
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| Platforms (1) |
| GPL2529 |
[Yeast_2] Affymetrix Yeast Genome 2.0 Array |
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| Samples (30)
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| GSM2714395 |
E9591_4H_Treated, biological repA |
| GSM2714396 |
E9591_4H_Treated, biological repB |
| GSM2714397 |
E9591_4H_Treated, biological repC |
| GSM2714398 |
LMT_4H_DMSO_Control, biological repA |
| GSM2714399 |
LMT_4H_DMSO_Control, biological repB |
| GSM2714400 |
LMT_4H_DMSO_Control, biological repC |
| GSM2714401 |
LMT_4H_Treated, biological repA |
| GSM2714402 |
LMT_4H_Treated, biological repB |
| GSM2714403 |
LMT_4H_Treated, biological repC |
| GSM2714404 |
E9591andLMT_15H_DMSO_Control, biological repA |
| GSM2714405 |
E9591andLMT_15H_DMSO_Control, biological repB |
| GSM2714406 |
E9591andLMT_15H_DMSO_Control, biological repC |
| GSM2714407 |
E9591_15H_Treated, biological repA |
| GSM2714408 |
E9591_15H_Treated, biological repB |
| GSM2714409 |
E9591_15H_Treated, biological repC |
| GSM2714410 |
LMT_15H_Treated, biological repA |
| GSM2714411 |
LMT_15H_Treated, biological repB |
| GSM2714412 |
LMT_15H_Treated, biological repC |
| GSM2714413 |
BIPRandPHEN_4H_DMSO_Control, biological repA |
| GSM2714414 |
BIPRandPHEN_4H_DMSO_Control, biological repB |
| GSM2714415 |
BIPRandPHEN_4H_DMSO_Control, biological repC |
| GSM2714416 |
BIPR_4H_Treated, biological repA |
| GSM2714417 |
BIPR_4H_Treated, biological repB |
| GSM2714418 |
BIPR_4H_Treated, biological repC |
| GSM2714419 |
PHEN_4H_Treated, biological repA |
| GSM2714420 |
PHEN_4H_Treated, biological repB |
| GSM2714421 |
PHEN_4H_Treated, biological repC |
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| Relations |
| BioProject |
PRJNA395347 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE101749_RAW.tar |
31.4 Mb |
(http)(custom) |
TAR (of CEL, CHP) |
| Processed data included within Sample table |
| Processed data provided as supplementary file |
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