Sulfur Assimilation Pathway: New Antifungal Targets

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DESCRIPTION (provided by applicant): Fungal infections, most commonly caused by Candida albicans, are currently the fourth leading cause of hospital-acquired bloodstream infections and are associated with the highest rate of attributed mortality. Numerous strategies have been forwarded to define new metabolic targets for the treatment of systemic C. albicans infections. Critically missing from the vast majority of these plans, however, is an understanding of fungal metabolism in vivo. One promising focus for anti-fungal drug development is the sulfur assimilation pathway. In the proposed study we will use a genetic approach to define how the organism assimilates sulfur in an animal model of disseminated infection. We propose to investigate the importance of pathways that lead to the reduction of sulfate to sulfide, the incorporation of sulfide into carbon acceptors, and the channeling of the latter towards the synthesis of cysteine and methionine. We will also determine whether these processes vary as a function of infection niche within the host. Based on the annotation of the Candida genome, it is clear that sulfur fluxes in the fungus (and for that matter in most infectious organisms) differ at several important points from those in humans. The proposed work will thus determine whether these differences merit attention as targets for novel therapies. PUBLIC HEALTH RELEVANCE: Fungal infections are increasingly important, often fatal complications of intrusive medical procedures ranging from the sustaining therapies for neonates to bone marrow transplantation, chemotherapy and deep surgical procedures. The proposed study will determine how Candida albicans, the most common fungal pathogen associated with hospital infections, assimilates and uses the essential nutrient-sulfur. Preliminary studies reinforce the hypothesis that the sulfur assimilation pathways, which include unique enzymes without mammalian counterpart, could, if better understood, define new targets for the development of new anti-fungal therapies.