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Aprepitant, an antiemetic agent, displays potent synergistic interactions with azole drugs against emerging multidrug-resistant Candida auris

ABSTRACT: Combination therapies can be a promising tool to augment the antifungal activity of azole drugs against resistant Candida species. Here, we report the interaction between aprepitant, an antiemetic agent, and azole drugs against different Candida species including the emerging multidrug-resistant C. auris. Particularly, aprepitant enhanced the antifungal activity of itraconazole against C. auris by reducing its minimum inhibitory concentration (MIC) by 2-8 folds. Using Caenorhabditis elegans as an in vivo infection model, the aprepitant/itraconazole combination significantly prolonged the survival of the infected nematodes by ~90% and reduced the fungal burden by ~92% relative to the untreated control. Interestingly, the aprepitant/itraconazole combination exerted a potent fungicidal activity against both planktonic and adherent C. auris biofilms. Further, aprepitant/itraconazole displayed broad-spectrum synergistic interactions against other medically important Candida species including C. albicans, C. krusie, C. tropicalis, and C. parapsilosis (ƩFICI ranged from 0.08 to 031). Comparative transcriptomic profiling indicated aprepitant/itraconazole interferes significantly with metal ions homeostasis and compromises the ROS (reactive oxygen species) detoxification ability of C. auris. This study presents aprepitant as a novel, potent and broad-spectrum azole chemosensitizing agent that warrants further investigation.

ORGANISM(S): [Candida] auris

PROVIDER: GSE148749 | GEO | 2020/10/19

REPOSITORIES: GEO

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Potent synergistic interactions between lopinavir and azole antifungal drugs against emerging multidrug-resistant Candida auris

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Project description:In this study, we designed a novel antifungal agent, PQA-Az-13 that demonstrated antifungal activity against C. auris biofilms. Cellular proteomics indicated that PQA-Az-13 partially or completely inhibited numerous enzymatic proteins in C. auris biofilms, particularly those involved in both amino acid biosynthesis and metabolism processes, as well as in general energy-producing processes. Due to its hydrophobic nature and limited aqueous solubility, PQA-Az-13 was encapsulated in cationic liposomes and characterized by biophysical and spectral techniques. PQA-Az-13 liposomes demonstrated enhanced antifungal activity levels against both C. auris in in vitro biofilms and ex vivo skin colonization models.

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Aprepitant, an antiemetic agent, displays potent synergistic interactions with azole drugs against emerging multidrug-resistant Candida auris

Project description:Aprepitant, an antiemetic agent, displays potent synergistic interactions with azole drugs against emerging multidrug-resistant Candida auris

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Set1-mediated histone H3K4 methylation is conserved and required for azole induction of ergosterol biosynthesis genes and antifungal drug resistance in Candida glabrata

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