Candidiasis is an opportunistic fungal infection that has high prevalence among immunocompromised individuals and is a common cause of neonatal bloodstream infections in premature infants. Candidiasis is a leading cause of fungal infections-related mortality in the neonatal intensive care unit. Candida albicans is the major fungal organism responsible for oral, cutaneous, genital and urinary tract infections, and systemic or disseminated disease with multi-organ involvement. The crude and attributable mortality rates associated with candidiasis and invasive candidal infections are very high. Despite antifungal treatment, 20% of infants who develop invasive candidiasis die, and neurodevelopmental impairment occurs in nearly 60% of survivors. Given the limited number of suitable and effective antifungal drugs, together with increasing resistance of the pathogens to azole antifungal agents culminate in the need for new antifungals. The development of therapeutic agents that have the ability to inhibit the biofilm formation and modulate inflammatory response can have major impact on the prevention and treatment of candidiasis. In this R21/R33 RFA titled ?Discovery/Development of Novel Therapeutics for Eukaryotic Pathogens? we propose to discover and develop natural product based agents as novel antifungal therapeutics. We will utilize a coculture strategy by culturing Candida albicans with individual organisms from large, well characterized bacterial and fungal collections. The hypothesis is that by mimicking the natural competition between two organisms we will be able to trigger the biosynthesis of the silent secondary metabolism pathways that will be able to inhibit C. albicans growth. Because of the large number of coculture experiments during the initial R21 stage, we propose to use a recently developed microfluidic device to increase the output of these coculture experiments for the identification of lead compounds. In the R33 stage of the project we propose to optimize top hits from the R21 phase of the project by engineering the biosynthetic pathways of the natural products. The translational significance of this work is that it could lead to a novel pharmacological therapeutic to prevent or treat candidiasis in humans.
The possibility of having a small molecule that inhibits C. albicans biofilm and modulates host inflammation (by promoting an anti-inflammatory response) is an exciting approach and will have major impact in terms of developing new therapeutic agents. In this project we will test the hypothesis that novel natural products based antifungal therapeutics could be discovered by leveraging the natural communication signals between pathogenic fungi and other organisms. In the development phase of the project we will generate analogs for further testing. These studies will validate the pharmacological effect of natural products in vitro and in vivo and will provide a solid biological foundation for translational research needed to prevent and treat fungal biofilm- related diseases in humans.