In vivo profiling for oral candidiasis drug target discovery

DESCRIPTION (provided by applicant): Candida albicans is the most frequently isolated fungal pathogen of humans and represents an important public health problem. However, antifungal treatments are hampered by emerging resistance, toxicity concerns, lack of fungicidal activity, and narrow spectrum of action. Thus, there is a critical need for new antifungal drug targets, and new antifungal drug strategies. An important step in the identification of new targets for antifungal drug discovery is the use of in vivo genome profiling using appropriate diseased samples to identify fungal-specific genes which are required for infection. The Phase I application successfully utilized emerging technologies to identify C. albicans genes induced during murine oral candidiasis. Specifically, we identified a subset of: (i) in vivo expressed genes; (ii) infection and colonization-associated genes, and (iii) novel and fungal-specific genes that will likely play a role in the transition from comced targets identified during the Phase I research are required for oral infection. Specific C. albicans knockout strains will be generated and assessed for their ability to cause disease during oral candidiasis. Specific Aim 2 will demonstrate that oligonucleotides can function as antifungal agents against Candida species in vitro. Oligonucleotides will be designed against pre-existing antifungal drug targets and against infection- required targets identified in Specific Aim 1. The oligonucleotides will be preferentially designed against domains within the gene open reading frame that are conserved amongst pathogenic fungi. The antifungal capability of the oligonucleotides will be assessed specifically at the mRNA level, and analyzed for the corresponding alterations in growth, viability, or specific phenotype trait. Specific Aim 3 will demonstrate that the oligonucleotides can be used alone, and in combination with known antifungal agents, to treat murine oral candidiasis. The rese Mucosal candidiasis is the mostcommon type of Candida infection and occurs frequently in immunocompromised patients, and patients with an altered bacterial flora. Despite the large number of at risk patients, antifungal treatment is hampered by toxic side effects and emerging antifungal resistant Candida strains and species.