Puupehenone, a Marine-Sponge-Derived Sesquiterpene Quinone, Potentiates the Antifungal Drug Caspofungin by Disrupting Hsp90 Activity and the Cell Wall Integrity Pathway

ABSTRACT 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 echi...

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Autores principales:	Siddharth K. Tripathi, Qin Feng, Li Liu, David E. Levin, Kuldeep K. Roy, Robert J. Doerksen, Scott R. Baerson, Xiaomin Shi, Xuewen Pan, Wen-Hui Xu, Xing-Cong Li, Alice M. Clark, Ameeta K. Agarwal
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	Hsp90 caspofungin cell wall integrity pathway potentiation Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/5135f27089314ab884d2181bb1856ca4
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spelling	oai:doaj.org-article:5135f27089314ab884d2181bb1856ca42021-11-15T15:27:53ZPuupehenone, a Marine-Sponge-Derived Sesquiterpene Quinone, Potentiates the Antifungal Drug Caspofungin by Disrupting Hsp90 Activity and the Cell Wall Integrity Pathway10.1128/mSphere.00818-192379-5042https://doaj.org/article/5135f27089314ab884d2181bb1856ca42020-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00818-19https://doaj.org/toc/2379-5042ABSTRACT 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 sequencing (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 mitogen-activated protein (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 cochaperone Cdc37. Thus, we show that PUUP potentiates CAS activity by a previously undescribed mechanism which involves a 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. IMPORTANCE Fungal infections cause more fatalities worldwide each year than malaria or tuberculosis. Currently available antifungal drugs have various limitations, including host toxicity, narrow spectrum of activity, and pathogen resistance. Combining these drugs with small molecules that can overcome these limitations is a useful strategy for extending their clinical use. We have investigated the molecular mechanism by which a marine-derived compound potentiates the activity of the antifungal echinocandin caspofungin. Our findings revealed a mechanism, different from previously reported caspofungin potentiators, in which potentiation is achieved by the disruption of Hsp90 activity and signaling through the cell wall integrity pathway, processes that play important roles in the adaptation to caspofungin in fungal pathogens. Given the importance of stress adaptation in the development of echinocandin resistance, this work will serve as a starting point in the development of new combination therapies that will likely be more effective and less prone to pathogen resistance.Siddharth K. TripathiQin FengLi LiuDavid E. LevinKuldeep K. RoyRobert J. DoerksenScott R. BaersonXiaomin ShiXuewen PanWen-Hui XuXing-Cong LiAlice M. ClarkAmeeta K. AgarwalAmerican Society for MicrobiologyarticleHsp90caspofungincell wall integrity pathwaypotentiationMicrobiologyQR1-502ENmSphere, Vol 5, Iss 1 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Hsp90 caspofungin cell wall integrity pathway potentiation Microbiology QR1-502
spellingShingle	Hsp90 caspofungin cell wall integrity pathway potentiation Microbiology QR1-502 Siddharth K. Tripathi Qin Feng Li Liu David E. Levin Kuldeep K. Roy Robert J. Doerksen Scott R. Baerson Xiaomin Shi Xuewen Pan Wen-Hui Xu Xing-Cong Li Alice M. Clark Ameeta K. Agarwal Puupehenone, a Marine-Sponge-Derived Sesquiterpene Quinone, Potentiates the Antifungal Drug Caspofungin by Disrupting Hsp90 Activity and the Cell Wall Integrity Pathway
description	ABSTRACT 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 sequencing (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 mitogen-activated protein (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 cochaperone Cdc37. Thus, we show that PUUP potentiates CAS activity by a previously undescribed mechanism which involves a 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. IMPORTANCE Fungal infections cause more fatalities worldwide each year than malaria or tuberculosis. Currently available antifungal drugs have various limitations, including host toxicity, narrow spectrum of activity, and pathogen resistance. Combining these drugs with small molecules that can overcome these limitations is a useful strategy for extending their clinical use. We have investigated the molecular mechanism by which a marine-derived compound potentiates the activity of the antifungal echinocandin caspofungin. Our findings revealed a mechanism, different from previously reported caspofungin potentiators, in which potentiation is achieved by the disruption of Hsp90 activity and signaling through the cell wall integrity pathway, processes that play important roles in the adaptation to caspofungin in fungal pathogens. Given the importance of stress adaptation in the development of echinocandin resistance, this work will serve as a starting point in the development of new combination therapies that will likely be more effective and less prone to pathogen resistance.
format	article
author	Siddharth K. Tripathi Qin Feng Li Liu David E. Levin Kuldeep K. Roy Robert J. Doerksen Scott R. Baerson Xiaomin Shi Xuewen Pan Wen-Hui Xu Xing-Cong Li Alice M. Clark Ameeta K. Agarwal
author_facet	Siddharth K. Tripathi Qin Feng Li Liu David E. Levin Kuldeep K. Roy Robert J. Doerksen Scott R. Baerson Xiaomin Shi Xuewen Pan Wen-Hui Xu Xing-Cong Li Alice M. Clark Ameeta K. Agarwal
author_sort	Siddharth K. Tripathi
title	Puupehenone, a Marine-Sponge-Derived Sesquiterpene Quinone, Potentiates the Antifungal Drug Caspofungin by Disrupting Hsp90 Activity and the Cell Wall Integrity Pathway
title_short	Puupehenone, a Marine-Sponge-Derived Sesquiterpene Quinone, Potentiates the Antifungal Drug Caspofungin by Disrupting Hsp90 Activity and the Cell Wall Integrity Pathway
title_full	Puupehenone, a Marine-Sponge-Derived Sesquiterpene Quinone, Potentiates the Antifungal Drug Caspofungin by Disrupting Hsp90 Activity and the Cell Wall Integrity Pathway
title_fullStr	Puupehenone, a Marine-Sponge-Derived Sesquiterpene Quinone, Potentiates the Antifungal Drug Caspofungin by Disrupting Hsp90 Activity and the Cell Wall Integrity Pathway
title_full_unstemmed	Puupehenone, a Marine-Sponge-Derived Sesquiterpene Quinone, Potentiates the Antifungal Drug Caspofungin by Disrupting Hsp90 Activity and the Cell Wall Integrity Pathway
title_sort	puupehenone, a marine-sponge-derived sesquiterpene quinone, potentiates the antifungal drug caspofungin by disrupting hsp90 activity and the cell wall integrity pathway
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/5135f27089314ab884d2181bb1856ca4
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Puupehenone, a Marine-Sponge-Derived Sesquiterpene Quinone, Potentiates the Antifungal Drug Caspofungin by Disrupting Hsp90 Activity and the Cell Wall Integrity Pathway

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