Eldesouky, Hassan E.Lanman, Nadia A.Hazbun, Tony R.Seleem, Mohamed N.2021-09-012021-09-012020-01-012150-5594http://hdl.handle.net/10919/104888With 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.Pages 1466-148116 page(s)application/pdfenCreative Commons Attribution 4.0 InternationalLife Sciences & BiomedicineImmunologyInfectious DiseasesMicrobiologyCandida aurisfungal biofilmsazole resistanceCaenorhabditis elegansmetal ion homeostasisreactive oxygen species (ROS)ALBICANS STRAINSANTIFUNGALIRONGENERATIONRESISTANCEDISCOVERYBIOFILMSPACKAGE0501 Ecological Applications0605 Microbiology1108 Medical MicrobiologyAnimalsCaenorhabditis elegansBiofilmsCandidaCandidiasisIonsMetalsAzolesAntiemeticsAntifungal AgentsMicrobial Sensitivity TestsGene Expression ProfilingDrug Resistance, Multiple, FungalHomeostasisDrug SynergismAprepitantArticle - Refereed2021-09-01https://doi.org/10.1080/21505594.2020.1838741111Seleem, Mohamed [0000-0003-0939-0458]331001492150-5608