Development and evaluation of a second-generation fungerp for systemic and cutaneous C. auris infection

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Candida auris has emerged as a global threat causing serious invasive infections with mortality approaching nearly 60 percent worldwide. The majority of C. auris infections are nosocomial and reportedly resistant to fluconazole (FLU) and amphotericin B (AmB) with variable resistance to members of the three major classes of clinically available antifungals (azoles, polyenes, echinocandins), with some strains resistant to all three antifungal classes, thereby limiting treatment options. C. auris has been classified as a ‘newly emerging threat’ by the Centers for Disease Control (CDC), although Candida albicans remains the most prevalent and pathogenic Candida species. With C. auris classified as a global urgent threat, and Candida spp. and other resistant fungal species emerging, there is a need to identify and develop new modalities to treat infections caused by Candida spp. Because C. auris colonizes the skin and acts as a nidus of infection, developing a drug that can concurrently target skin and exhibit systemic efficacy will be highly innovative and desirable. A triterpenoid class of antifungals derived from enfumafungin, a hemiacetal isolated from fermentation of Hormonema spp. (generically termed fungerps), represents the first newly described class of antifungal compounds since 2001. Currently, a second-generation fungerp, SCY-247, is under development as a potential systemic therapeutic option. Because the skin is a natural niche for C. auris, and transmission occurs through cutaneous contact, demonstrating that SCY-247, in addition to working systemically (including at the blood brain barrier), is effective as a cutaneous (i.e., decolonization) treatment for C. auris is innovative. We hypothesize that our preclinical models of systemic and cutaneous C. auris infection, will allow us to demonstrate the efficacy of SCY-247 as a new therapeutic treatment for skin as well as disseminated infection including brain infection. Thus, our multi-pronged approach includes three specific aims designed to: 1) Determine the effective in vitro and in vivo range of SCY-247 that is inhibitory/fungicidal to Candida strains resistant to traditional antifungal therapy with an emphasis on C. auris strains; and 2) Employ established cutaneous guinea pig and murine models of C. auris to address treatment and decolonization approaches using SCY-247, and finally; 3) Determine the efficacy of SCY-247 in the treatment of central nervous system (CNS) infection caused by C. auris or C. albicans spp. using an intracranial murine model and high-resolution intravital microscopy (IVM). Successful completion of these aims will determine whether SCY-247 is a viable option for eradication of C. auris, and whether this compound is effective against known resistant Candida spp. We will evaluate both oral and I.V. dosing of SCY-247 comparing their potential efficacy. Finally, the ability of SCY-247 to treat C. auris brain infection will be assessed. Successful completion of these preclinical studies will enable advancing SCY-247 into Phase 1 clinical trials.