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 of Cryptococcus 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 pathogenic Cryptococcus species, 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 inhibited Cryptococcus, nisoldipine was also effective against Candida, Saccharomyces and Aspergillus. This study validates repurposing as a rapid approach for finding new agents to treat neglected infectious diseases.
Highlights
Cryptococcal meningitis is a devastating fungal disease that disproportionately affects the poorest, most resource-limited, underdeveloped regions of the world, where the health burden is extremely high
Stock solutions of amphotericin B, itraconazole and voriconazole were prepared at 1.6 mg/mL in water; 5-flucytosine was made at 6.4 mg/mL in water; fluconazole was made at 12.8 mg/mL in water and all remaining drugs were dissolved in dimethyl sulfoxide (DMSO) at 2 mg/mL
Using the selection criteria described in the “Methods” section, 16 of the remaining compounds identified in the primary screen were short-listed for further evaluation by minimum inhibitory concentration (MIC) assays against C. deuterogattii
Summary
Cryptococcal meningitis is a devastating fungal disease that disproportionately affects the poorest, most resource-limited, underdeveloped regions of the world, where the health burden is extremely high. Mortality rates are unacceptably high and vary significantly with demography, with estimates as low as 9% among patients in developed countries compared to 70% in sub-Saharan Africa (Park et al, 2009), where cryptococcal meningitis clinically presents in up to 40% of HIV/AIDS patients (Dzoyem et al, 2012; Rajasingham et al, 2017) This high mortality is largely attributable to lack of access and difficulty in administering the most effective standard treatment, amphotericin B combined with flucytosine (Kneale et al, 2016; Perfect et al, 2010), which is expensive and requires medical infrastructure for therapeutic monitoring due to adverse effects including nephrotoxicity, hepatotoxicity and bone marrow suppression (Kneale et al, 2016; Loyse et al, 2013; Meiring et al, 2016). Sertraline achieved more efficient clearance of fungal burden in HIV-infected patients in Uganda, with no relapse during the clinical study (Rhein et al, 2016)
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