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Overcoming amphotericin B resistance in Candida auris using the antiemetic drug rolapitant
Ehab A Salama1,2, Yehia Elgammal1,2, Sagar M Utturkar3
1Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA.
Abstract:
The emergence of Candida auris poses a significant health challenge that has led to a new era of multidrug-resistant fungal infections. Invasive infections caused by C. auris are usually associated with remarkable morbidity and mortality. For many years, amphotericin B (AmB) remained the most efficient and the last line of treatment against most hard-to-treat fungal infections. However, strains of C. auris possess extraordinary resistance to most antifungal agents, including AmB. In this study, we screened ~2,600 FDA-approved drugs and clinical compounds to identify the antiemetic drug rolapitant as a promising enhancer to AmB against C. auris. Rolapitant exhibited potent synergistic interactions with AmB against all tested (29/29) C. auris isolates. In a time-kill assay, rolapitant restored the fungicidal activity of AmB within 4 h. Additionally, the synergistic relationship between rolapitant and AmB was observed against other medically crucial Candida, Cryptococcus, and Aspergillus species. A transcriptomic study revealed that exposure to rolapitant affects oxidation reduction processes, ion transporters, and ATP production. Rolapitant triggers an elevation in cytosolic and mitochondrial calcium levels and induces oxidative stress within fungal cells. An ATP luminescence assay confirmed that rolapitant, at sub-inhibitory concentrations, significantly interfered with ATP production in C. auris. Moreover, rolapitant enhanced the in vivo activity of AmB in a mouse model of disseminated C. auris infection, as the combination reduced the fungal burden in murine kidneys by ~1 log (~90%) colony forming units. Our findings warrant further investigation of using rolapitant to overcome AmB resistance in C. auris and other fungal species.
Insights
The antiemetic drug rolapitant enhances amphotericin B (AmB) efficacy against multidrug-resistant Candida auris. This combination restores AmB
Area of Science:
- Mycology and Infectious Diseases
- Antifungal Drug Discovery and Development
Background:
- Emergence of multidrug-resistant Candida auris presents a critical global health threat, causing severe invasive infections with high mortality.
- Amphotericin B (AmB) is a last-resort antifungal, but resistance in Candida auris limits its effectiveness.
Purpose of the Study:
- To identify existing drugs that can enhance the activity of amphotericin B against multidrug-resistant Candida auris.
- To investigate the synergistic potential of rolapitant in combination with amphotericin B against Candida auris and other fungal pathogens.
Main Methods:
- Screened approximately 2,600 FDA-approved drugs and clinical compounds for synergistic effects with amphotericin B against Candida auris.
- Utilized time-kill assays, transcriptomic analysis, ATP luminescence assays, and a murine model of disseminated infection to evaluate drug efficacy and mechanisms.
Main Results:
- Identified the antiemetic drug rolapitant as a potent enhancer of amphotericin B against all tested Candida auris isolates, restoring fungicidal activity.
- Demonstrated synergistic interactions between rolapitant and amphotericin B against other key fungal species, including Candida, Cryptococcus, and Aspergillus.
- Showed rolapitant enhances amphotericin B's in vivo efficacy, significantly reducing fungal burden in a mouse model of Candida auris infection.
Conclusions:
- Rolapitant exhibits significant synergistic activity with amphotericin B against multidrug-resistant Candida auris and other pathogenic fungi.
- Rolapitant's mechanism involves interfering with fungal ATP production, elevating calcium levels, and inducing oxidative stress.
- Rolapitant represents a promising therapeutic strategy to overcome amphotericin B resistance in challenging fungal infections.
