Development of Broad Spectrum Antifungal Agents

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ABSTRACT Candidiasis is a fungal infection caused by yeasts that belong to the genus Candida. Candida yeasts normally reside in the mouth, intestines and on the skin of all humans and do not pose an immediate threat to the average immunocompetent person. However, Candida can cause opportunistic and frequently life-threatening conditions in immunocompromised individuals or under conditions in which healthy bacteria levels are disrupted, especially in hospital settings. Overall, Candida spp. are responsible for roughly 10% of all blood infections with a mortality rate of 20-50%. The number of cases of invasive candidiasis is expected to rise with increased numbers of aging and immunosuppressed individuals in the population. Numerous over-the-counter agents are available for treating less severe symptoms of the skin and genital and urinary tracts; however, treatment options for systemic infections are limited by toxicity of front line therapy and increasing rates of resistance. Although C. albicans has historically been the most prominent Candida species, it is now recognized that other Candida species are increasing in prevalence with C. albicans, C. glabrata, C. tropicalis, C. parapsilosis and C. krusei considered the most virulent. The highest rates of antifungal drug resistance are associated with C. glabrata, which is intrinsically resistant to both common classes of antifungal agents, accounting for more than 70% of all echinocandin- resistant isolates and over 90% of all multidrug-resistant isolates. We have formed a new start-up venture, Quercus Molecular Design (QMD LLC), whose long-term objective is to identify, characterize, and exploit infectious disease drug targets for the treatment of the immunologically vulnerable. Since DHFR is highly conserved among fungal species, fungi-specific folate antimetabolites are anticipated to have broad spectrum activity against multiple Candida species. We hypothesize that it will be possible to develop dihydrofolate reductase (DHFR) inhibitors that inhibit multiple Candida species. This phase I proposal is based on exciting preliminary data indicating that small molecule lead compounds exhibit high levels of specificity for the fungal DHFR enzyme over the human counterpart and also exhibit excellent antifungal activity against C. albicans and C. glabrata. The purpose of this Phase 1 STTR is to determine the feasibility of developing a broadly active treatment for multiple species of Candida. To that end, efficacy of the lead series will be evaluated against isolates of Candida spp., including drug-resistant strains and the lead series will be expanded through a focused medicinal chemistry effort and tested for efficacy in vitro and in cell culture. This phase I proposal is based on a decade of work from Dr. Dennis Wright’s laboratory focused on small-molecule drug discovery in infectious disease. This proposal also leverages Dr. Lee Wright’s nearly 20 years of experience in the areas of pharmaceutical medicinal chemistry and small-molecule drug development and Dr. Michael Cynamon’s multiple decades of clinical work in the identification, evaluation and treatment of fungal disease. Our long-term goal is to develop the most promising lead compounds to create a broadly-acting Candida therapeutic.