Abstract
Due to the increasing prevalence of pathogenic fungal infections, the emergence of antifungal resistant clinical isolates worldwide, and the limited arsenal of available antifungals, developing new antifungal strategies is imperative. In this study, we screened a library of 1068 FDA-approved drugs to identify hits that exhibit broad-spectrum antifungal activity. Robenidine, an anticoccidial agent which has been widely used to treat coccidian infections of poultry and rabbits, was identified in this screen. Physiological concentration of robenidine (8 μM) was able to significantly inhibit yeast cell growth, filamentation and biofilm formation of Candida albicans – the most extensively studied human fungal pathogen. Moreover, we observed a broad-spectrum antifungal activity of this compound against fluconazole resistant clinical isolates of C. albicans, as well as a wide range of other clinically relevant fungal pathogens. Intriguingly, robenidine-treated C. albicans cells were hypersensitive to diverse cell wall stressors, and analysis of the cell wall structure by transmission electron microscopy (TEM) showed that the cell wall was severely damaged by robenidine, implying that this compound may target the cell wall integrity signaling pathway. Indeed, upon robenidine treatment, we found a dose dependent increase in the phosphorylation of the cell wall integrity marker Mkc1, which was decreased after prolonged exposure. Finally, we provide evidence by RNA-seq and qPCR that Rlm1, the downstream transcription factor of Mkc1, may represent a potential target of robenidine. Therefore, our data suggest that robenidine, a FDA approved anti-coccidiosis drug, displays a promising and broadly effective antifungal strategy, and represents a potentially repositionable candidate for the treatment of fungal infections.
Highlights
Fungal infections pose a global threat to human health
The drug identified with the largest inhibitory effect against C. albicans was robenidine
At 32 μM concentration (11.86 μg/ml), robenidine, but not fluconazole, was able to completely inhibit growth of C. albicans. These results indicate that robenidine is effective in inhibiting C. albicans growth
Summary
Fungal infections pose a global threat to human health. Billions of people around the world suffer from fungal infections, resulting in more than 1.5 million deaths. Candida albicans is the most frequently isolated human fungal pathogen in the clinic (Martin et al, 2003; Zaoutis et al, 2005; Pfaller and Diekema, 2007). The mortality rate of bloodstream infections caused by C. albicans is 40–70% (Wenzel, 1995), especially in severely immunocompromised patients. The existing arsenal of antifungals to treat these lifethreatening infections is very limited, with some therapeutics exhibiting a narrow spectrum of activity, and/or severe sideeffects (Pina-Vaz et al, 2004). The emergence of antifungal-resistant fungal isolates is an increasing concern (Butler and Buss, 2006; Lam, 2007). Identifying new antifungals drugs and their targets represents an urgent need in the field
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