Aprepitant, an antiemetic agent, interferes with metal ion homeostasis of Candida auris and displays potent synergistic interactions with azole drugs

With the rapid increase in the frequency of azole-resistant species, combination therapy appears to be a promising tool to augment the antifungal activity of azole drugs against resistant Candida species. Here, we report the effect of aprepitant, an antiemetic agent, on the antifungal activities of...

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Autores principales:	Hassan E. Eldesouky, Nadia A. Lanman, Tony R. Hazbun, Mohamed N. Seleem
Formato:	article
Lenguaje:	EN
Publicado:	Taylor & Francis Group 2020
Materias:	candida auris fungal biofilms azole resistance caenorhabditis elegans metal ion homeostasis reactive oxygen species (ros) Infectious and parasitic diseases RC109-216
Acceso en línea:	https://doaj.org/article/45a4196d185a46b78c360bf6857c3d82
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spelling	oai:doaj.org-article:45a4196d185a46b78c360bf6857c3d822021-11-17T14:21:59ZAprepitant, an antiemetic agent, interferes with metal ion homeostasis of Candida auris and displays potent synergistic interactions with azole drugs2150-55942150-560810.1080/21505594.2020.1838741https://doaj.org/article/45a4196d185a46b78c360bf6857c3d822020-12-01T00:00:00Zhttp://dx.doi.org/10.1080/21505594.2020.1838741https://doaj.org/toc/2150-5594https://doaj.org/toc/2150-5608With the rapid increase in the frequency of azole-resistant species, combination therapy appears to be a promising tool to augment the antifungal activity of azole drugs against resistant Candida species. Here, we report the effect of aprepitant, an antiemetic agent, on the antifungal activities of azole drugs against the multidrug-resistant Candida auris. Aprepitant reduced the minimum inhibitory concentration (MIC) of itraconazole in vitro, by up to eight-folds. Additionally, the aprepitant/itraconazole combination interfered significantly with the biofilm-forming ability of C. auris by 95 ± 0.13%, and significantly disrupted mature biofilms by 52 ± 0.83%, relative to the untreated control. In a Caenorhabditis elegans infection model, the aprepitant/itraconazole combination significantly prolonged the survival of infected nematodes by ~90% (five days post-infection) and reduced the fungal burden by ~92% relative to the untreated control. Further, this novel drug combination displayed broad-spectrum synergistic interactions against other medically important Candida species such as C. albicans, C. krusei, C. tropicalis, and C. parapsilosis (ƩFICI ranged from 0.08 to 0.31). Comparative transcriptomic profiling and mechanistic studies indicated aprepitant/itraconazole interferes significantly with metal ion homeostasis and compromises the ROS detoxification ability of C. auris. This study presents aprepitant as a novel, potent, and broad-spectrum azole chemosensitizing agent that warrants further investigation.Hassan E. EldesoukyNadia A. LanmanTony R. HazbunMohamed N. SeleemTaylor & Francis Grouparticlecandida aurisfungal biofilmsazole resistancecaenorhabditis elegansmetal ion homeostasisreactive oxygen species (ros)Infectious and parasitic diseasesRC109-216ENVirulence, Vol 11, Iss 1, Pp 1466-1481 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	candida auris fungal biofilms azole resistance caenorhabditis elegans metal ion homeostasis reactive oxygen species (ros) Infectious and parasitic diseases RC109-216
spellingShingle	candida auris fungal biofilms azole resistance caenorhabditis elegans metal ion homeostasis reactive oxygen species (ros) Infectious and parasitic diseases RC109-216 Hassan E. Eldesouky Nadia A. Lanman Tony R. Hazbun Mohamed N. Seleem Aprepitant, an antiemetic agent, interferes with metal ion homeostasis of Candida auris and displays potent synergistic interactions with azole drugs
description	With the rapid increase in the frequency of azole-resistant species, combination therapy appears to be a promising tool to augment the antifungal activity of azole drugs against resistant Candida species. Here, we report the effect of aprepitant, an antiemetic agent, on the antifungal activities of azole drugs against the multidrug-resistant Candida auris. Aprepitant reduced the minimum inhibitory concentration (MIC) of itraconazole in vitro, by up to eight-folds. Additionally, the aprepitant/itraconazole combination interfered significantly with the biofilm-forming ability of C. auris by 95 ± 0.13%, and significantly disrupted mature biofilms by 52 ± 0.83%, relative to the untreated control. In a Caenorhabditis elegans infection model, the aprepitant/itraconazole combination significantly prolonged the survival of infected nematodes by ~90% (five days post-infection) and reduced the fungal burden by ~92% relative to the untreated control. Further, this novel drug combination displayed broad-spectrum synergistic interactions against other medically important Candida species such as C. albicans, C. krusei, C. tropicalis, and C. parapsilosis (ƩFICI ranged from 0.08 to 0.31). Comparative transcriptomic profiling and mechanistic studies indicated aprepitant/itraconazole interferes significantly with metal ion homeostasis and compromises the ROS detoxification ability of C. auris. This study presents aprepitant as a novel, potent, and broad-spectrum azole chemosensitizing agent that warrants further investigation.
format	article
author	Hassan E. Eldesouky Nadia A. Lanman Tony R. Hazbun Mohamed N. Seleem
author_facet	Hassan E. Eldesouky Nadia A. Lanman Tony R. Hazbun Mohamed N. Seleem
author_sort	Hassan E. Eldesouky
title	Aprepitant, an antiemetic agent, interferes with metal ion homeostasis of Candida auris and displays potent synergistic interactions with azole drugs
title_short	Aprepitant, an antiemetic agent, interferes with metal ion homeostasis of Candida auris and displays potent synergistic interactions with azole drugs
title_full	Aprepitant, an antiemetic agent, interferes with metal ion homeostasis of Candida auris and displays potent synergistic interactions with azole drugs
title_fullStr	Aprepitant, an antiemetic agent, interferes with metal ion homeostasis of Candida auris and displays potent synergistic interactions with azole drugs
title_full_unstemmed	Aprepitant, an antiemetic agent, interferes with metal ion homeostasis of Candida auris and displays potent synergistic interactions with azole drugs
title_sort	aprepitant, an antiemetic agent, interferes with metal ion homeostasis of candida auris and displays potent synergistic interactions with azole drugs
publisher	Taylor & Francis Group
publishDate	2020
url	https://doaj.org/article/45a4196d185a46b78c360bf6857c3d82
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Aprepitant, an antiemetic agent, interferes with metal ion homeostasis of Candida auris and displays potent synergistic interactions with azole drugs

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