Repurposing drugs to fast-track therapeutic agents for the treatment of cryptococcosis

Abstract

Many infectious diseases disproportionately affect people in the developing world. Cryptococcal meningitis is one of the most common mycoses in HIV-AIDS patients, with the highest burden of disease in sub-Saharan Africa. Current best treatment regimens still result in unacceptably high mortality rates, and more effective antifungal agents are needed urgently. Drug development is hampered by the difficulty of developing effective antifungal agents that are not also toxic to human cells, and by a reluctance among pharmaceutical companies to invest in drugs that cannot guarantee a high financial return. Drug repurposing, where existing drugs are screened for alternative activities, is becoming an attractive approach in antimicrobial discovery programs, and various compound libraries are now commercially available. As these drugs have already undergone extensive optimisation and passed regulatory hurdles this can fast-track their progress to market for new uses. This study screened the Screen-Well Enzo library of 640 compounds for candidates that phenotypically inhibited the growth ofCryptococcus deuterogattii. The anthelminthic agent flubendazole, and L-type calcium channel blockers nifedipine, nisoldipine and felodipine, appeared particularly promising and were tested in additional strains and species. Flubendazole was very active against all pathogenicCryptococcusspecies, with minimum inhibitory concentrations of 0.039–0.156 μg/mL, and was equally effective against isolates that were resistant to fluconazole. While nifedipine, nisoldipine and felodipine all inhibitedCryptococcus, nisoldipine was also effective againstCandida, SaccharomycesandAspergillus. This study validates repurposing as a rapid approach for finding new agents to treat neglected infectious diseases.