Repurposing of Ribavirin as an Adjunct Therapy against Invasive Candida Strains in an In Vitro Study

Abstract

The use of antifungal agents in clinical settings is limited by the appearance of drug resistance and adverse side effects. There is, therefore, an urgent need to develop new drugs to strengthen the treatment of invasive fungal diseases. The aim of this study is to describe the potential repurposing of ribavirin as an adjunct therapy against Candida spp. Primary screening of a Prestwick Chemical library against Candida albicans ATCC 90028 and fluconazole-resistant Candida albicans strains was performed. Subsequently, we evaluated the responses of 100 Candida sp. strains to ribavirin, an antiviral agent, using the broth microdilution method as recommended by CLSI. We checked the involvement of efflux pump activity in the development of ribavirin resistance. We studied time-kill curves and performed a checkerboard assay for a ribavirin-antifungal combination study. Twenty-one nonstandard antifungal compounds were identified, including ribavirin. Ribavirin had antifungal activity in vitro against 63 Candida strains, including strains of C. albicans, C. parapsilosis, and C. tropicalis, with MICs ranging from 0.37 to 3.02 μg/ml, while MICs for C. krusei, C. glabrata, C. lusitaniae, and some C. albicans strains remained high (≥24.16 μg/ml). No relation was observed between efflux pump activity and ribavirin resistance. Ribavirin exhibited fungistatic activity against multidrug-resistant (MDR) C. albicans and fungicidal activity against a C. parapsilosis strain. In addition, ribavirin acted synergistically with azoles against Candida strains for which ribavirin MICs were <24.4 μg/ml. This study highlights the potential clinical application of ribavirin, alone or in association with other antifungal agents, as an adjunct anti-Candida drug.

Identification of Off-Patent Drugs That Show Synergism with Amphotericin B or That Present Antifungal Action against Cryptococcus neoformans and Candida spp

“…A variation of these screenings is to test the activity of off-patent compounds, which is known as drug repurposing. The repurposing strategy has also been applied to look for active compounds (AC) against fungi, such as Candida albicans (21)(22)(23)(24)(25)(26), C. neoformans (26)(27)(28), the emerging pathogen Candida auris (26,29,30), and multiresistant molds such as Lomentospora prolificans (26).…”

Screening Repurposing Libraries for Identification of Drugs with Novel Antifungal Activity

“…), as well as molds, including some highly resistant emerging pathogens such as those in the genera Scedosporium and Lomentospora (50). Another screen of the Prestwick Chemical Library against two C. albicans strains, one being fluconazole and echinocandin resistant, identified ribavirin as the best option for repurposing (51). Ribavirin was shown to have activity against several Candida species, including those with drug resistance, but further elucidation is needed.…”

In Vitro Characterization of Twenty-One Antifungal Combinations against Echinocandin-Resistant and -Susceptible Candida glabrata

“…Among fungal infections, special attention has been paid to Candida spp. infections, which were identified as the major cause of bloodstream infections in hospitalized patients [ 2 ]. C. glabrata is one of the most prevalent fungal pathogens worldwide and is considered the second most-common fungal cause of candidemia in the United States [ 3 ].…”

“…Infections with C. glabrata are complicated as only few effective antifungal agents are available, due to its limited susceptibility to fluconazole [ 7 ]. For instance, since the discovery of the first antifungal agent (amphotericin B; 1950s) [ 8 ], only three antifungal classes (azoles, polyenes, and echinocandins) are currently indicated for the treatment of invasive candidiasis [ 2 ]. Echinocandins (caspofungin, micafungin, and anidulafungin) are used as first-line therapy for invasive candidiasis and act by inhibiting fungal cell wall synthesis through non-competitive inhibition of 1, 3-β- d -glucan synthase [ 3 ].…”