Homocitrate Synthase Inhibitors as Novel Antifungal Agents for Aspergillus

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DESCRIPTION (provided by applicant): Aspergillus fumigatus is a prevalent fungal pathogen that primarily infects individuals through inhalation of spores that subsequently germinate and send invasive hyphal extensions throughout the lungs, resulting in clinical bronchopulmonary and invasive aspergillosis. Individuals who are immunocompromised, such as burn patients, transplant recipients, cancer patients undergoing chemotherapy, and individuals suffering from HIV/AIDS or other immunodeficiency syndromes, as well as those suffering from chronic lung disease, such as cystic fibrosis, exhibit a higher risker of developing aspergillosis. In addition, individuals with fungal hypersensitivity are susceptible to developing allergic bronchopulmonary aspergillosis or severe asthma with fungal sensitization. Current antifungal therapies are generally unsuitable for the treatment of aspergillosis due to the toxicity and side effects associated with these drugs. These shortcomings underscore an urgent clinical need to develop new antifungal drugs that offer greater efficacy and a lower toxicity profile. One such target for drug development is homocitrate synthase (HCS), the enzyme that catalyzes the first and committed step in lysine biosynthesis in fungi. HCS is conserved in A. fumigatus, but is absent in humans, rendering it an attractive target for antifungal intervention. Further, recent studies have demonstrated that HCS is essential to the bronchopulmonary virulence of A. fumigatus, validating this enzyme as a novel target for antifungal drug design. The overall objective of this proposal is to identify and characterize homocitrate synthase inhibitors that block the growth of A. fumigatus. Toward this objective, we propose the following specific aims: 1) to identify of small molecule inhibitors of A. fumigatus HCS by in vitro high-throughput screening and 2) to assess the efficacy of these compounds in inhibiting A. fumigatus growth. We envision that these studies will yield chemical probes for studying aspergillosis in cell-based and animal models and provide a basis for developing new therapeutics for treating a spectrum of bronchopulmonary diseases caused by A. fumigatus.