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.
