Aprepitant, an antiemetic agent, interferes with metal ion homeostasis ofCandida aurisand displays potent synergistic interactions with azole drugs

Abstract

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.

What Do We Know about Candida auris? State of the Art, Knowledge Gaps, and Future Directions

“…There is growing evidence of the efficacy and effectivity of combination regimes, using echinocandins with a second or even third drug, such as amphotericin B, flucytosine, voriconazole, or isavuconazole, among others [ 156 , 157 ]. Less frequently, combinations with other drugs such as co-trimoxazole [ 158 ], lopinavir [ 159 ], aprepitant [ 160 ], or suloctidil [ 161 ] have been used. However, many of these results have been obtained in vitro, and need to be further validated in vivo.…”

Promising Drug Candidates and New Strategies for Fighting against the Emerging Superbug Candida auris

“…The combination aprepitant/itraconazole is particularly efficient in an in vivo C. elegans model of infection by C. auris . This synergistic relationship could be mediated by interferences with metal ion homoestasis and subsequent impact on ROS production [ 69 ]. The same team also reported that lopinavir, an HIV protease inhibitor, is able to chemosensitize azole drug.…”

Candida auris: A Quick Review on Identification, Current Treatments, and Challenges

“…Another case of drug repurposing is aprepitant, an agent helping to prevent nausea and vomiting, and on the other hand to enhance antifungal effects of azoles against C. auris by chemosensitizing [114]. Authors reported interference of aprepitant/itraconazole with metal ion homeostasis, which led to losing reactive oxygen species' detoxification ability [114]. [115,116] Biofilms formed by Candida spp.…”

“…Findings of a similar work indicate synergistic interactions between suloctidil (sulfur-containing aminoalcohol, vasodilator) and Vcz, and between ebselen (a synthetic organoselenium molecule) and anidulafungin [ 113 ]. Another case of drug repurposing is aprepitant, an agent helping to prevent nausea and vomiting, and on the other hand to enhance antifungal effects of azoles against C. auris by chemosensitizing [ 114 ]. Authors reported interference of aprepitant/itraconazole with metal ion homeostasis, which led to losing reactive oxygen species‘ detoxification ability [ 114 ].…”