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| Status |
Public on Dec 04, 2019 |
| Title |
Investigating the mechanism by which the natural product compound puupehenone potentiates the antifungal drug caspofungin |
| Organism |
Saccharomyces cerevisiae |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
The cell wall-targeting echinocandin antifungals, although potent and well-tolerated, are inadequate in treating fungal infections due to their narrow spectrum of activity and their propensity to induce pathogen resistance. A promising strategy to overcome these drawbacks is to combine echinocandins with a molecule that improves their activity and also disrupts drug adaptation pathways. In this study, we show that puupehenone (PUUP), a marine sponge-derived sesquiterpene quinone potentiates the echinocandin drug, caspofungin (CAS) in CAS-resistant fungal pathogens. We have conducted RNA-Seq analysis, followed by genetic and molecular studies, to elucidate PUUP’s CAS-potentiating mechanism. We found that the combination of CAS and PUUP blocked the induction of CAS-responding genes required for the adaptation to cell wall stress through the cell wall integrity (CWI) pathway. Further analysis showed that PUUP inhibited the activation of Slt2 (Mpk1), the terminal MAP kinase in this pathway. We also found that PUUP induced heat shock response genes and inhibited the activity of heat shock protein 90 (Hsp90). Molecular docking studies predicted that PUUP occupies a binding site on Hsp90 required for the interaction between Hsp90 and its co-chaperone Cdc37. Thus, we show that PUUP potentiates CAS activity by a previously undescribed mechanism which involves disruption of Hsp90 activity and the CWI pathway. Given the requirement of the Hsp90-Cdc37 complex in Slt2 activation, we suggest that inhibitors of this complex would disrupt the CWI pathway and synergize with echinocandins. Therefore, the identification of PUUP’s CAS-potentiating mechanism has important implications in the development of new antifungal combination therapies.
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| Overall design |
Gene expression profiles of Saccharomyces cerevisiae cells treated with caspofungin (CAS), puupehenone (PUUP), and caspofungin + puupehenone (CAS + PUUUP).
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| Contributor(s) |
Agarwal AK |
| Citation(s) |
31915228 |
| |
| Submission date |
Nov 18, 2019 |
| Last update date |
Jan 21, 2020 |
| Contact name |
Ameeta Agarwal |
| E-mail(s) |
aagarwal@olemiss.edu
|
| Phone |
662-915-1218
|
| Organization name |
University of Mississippi
|
| Department |
National Center for Natural Products Research
|
| Street address |
NCNPR, Room 2049
|
| City |
University |
| State/province |
MS |
| ZIP/Postal code |
38677 |
| Country |
USA |
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| Platforms (1) |
| GPL19756 |
Illumina NextSeq 500 (Saccharomyces cerevisiae) |
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| Samples (12)
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| Relations |
| BioProject |
PRJNA590180 |
| SRA |
SRP230416 |
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