Candida auris (C. auris) is an emerging pathogenic fungal species that exhibits a multi-drug resistant phenotype and has been the source organism for several outbreaks in healthcare facilities worldwide. Indeed, researchers at the Centers for Disease Control (CDC) have proclaimed C. auris ?the new kid on the block? in reference to all of the unknown aspects of this fungus, and the atypical phenotypic profile compared to other fungal species. Unusual points regarding C. auris include; ability to act as a nidus of infection through human skin; an independent emergence of four separate populations on three continents; the inability to identify the organism by most standard techniques (except DNA sequencing and advanced MALDI-TOF MS approaches), the frequent misidentification as C. haemulonii; and aggressive antifungal resistance that has been summarized by the CDC as ?concerning?. Our preliminary investigation of C. auris revealed a reduced production of biofilm formation and decreased adherence as compared to C. albicans, suggesting that C. auris may use alternative pathogenic mechanism(s) to infect host. Given the concerning profile of antifungal resistance to all classes of known antifungal therapeutics, it is of paramount importance to identify new therapies with efficacy toward C. auris. To address this need, we performed preliminary studies using a new semisynthetic derivative of the natural product enfumafungin, a fungal beta-1,3-D-glucan synthase inhibitor termed SCY-078. Our preliminary data indicated that SCY-078 was capable of blocking C. auris cell division, and possessed potent anti-biofilm activity, however, certain strains of C. auris were less susceptible to SCY-078. In order to identify new, potentially better antifungal agents capable of inhibiting C. auris, we screened newly synthesized structurally modified SCY-078 analogues (n=27) for minimal inhibitory concentration (MIC) and minimal fungicidal concentration (MFC) on 5 clinical isolates. We identified 3 SCY- 078 analogues with better efficacy toward C. auris than the parent SCY-078 compound. We seek to expand our pool of clinical isolates to improve rigor and ensure that the observed killing is not strain-specific. Expanding our clinical isolate pool (from different geographic regions and susceptibility profiles to current antifungals) will help to improve the reproducibility of MIC/MFC calculations and narrow our analogue selection to the most efficacious compound. Identification of compound(s) with improved distribution may also identify reagents capable of treating cutaneous C. auris infections, as modeled in our murine disseminated and guinea pig cutaneous C. auris models. The following specific aims address the critical need to advance better antifungal agents and improve our understanding of their distribution and potential mechanism(s) of resistance to therapy; 1) Determine the antifungal susceptibility of C. auris clinical isolates to SCY-078 analogues; 2) Determine the distribution of the SCY-078 analogues in vivo using disseminated and cutaneous models of candida infection; and 3) Determine potential development of therapeutic resistance to SCY-078 analogues.
Candida auris (C auris) is an unusually aggressive pathogenic fungal species that has been shown to be resistant to all major classes of antifungals. Given the atypical profile of C auris, its? high associated mortality and difficulty in eradicating it from cutaneous commensal niche where it acts as a nidus of infection; identification of new therapies targeting systemic and cutaneous infections with greater efficacy toward C auris are urgently needed. Thus, our project is designed to evaluate select analogues of a fungal beta-1,3-D-glucan synthase inhibitor (SCY-078) in vitro (>100 clinical isolates) and in vivo in order to narrow our analogue selection to the most efficacious compound.
