Targeting hybrid histidine kinase for broad spectrum antifungal therapy

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DESCRIPTION (provided by applicant): This challenge grant addresses the broad challenge area (03) "Biomarker Discovery and Validation". The challenge topic is 03-AI-101, entitled "Identification, characterization and evaluation of novel pathogen or host targets that may lead to the development of antimicrobials with broad-spectrum activity." The title of the proposal is: Targeting hybrid histidine kinase for broad-spectrum antifungal therapy. Despite the growing prevalence of severe fungal infections, we have a paucity of anti-fungal drugs, most of them are fraught with toxicity due to cross-reactivity with shared mammalian host targets, and only one new class of anti-fungal has been developed in the last decade. This proposal is designed to capitalize on a recent path-breaking discovery that a hybrid histidine kinase regulates global control of dimorphism and virulence in fungi. We hypothesize that hybrid histidine kinase represents an ideal target for the development of anti- fungal drugs to treat patients. This new target offers many features that the field has been seeking for development of broad-spectrum anti-fungal drugs, since it is highly conserved throughout the fungal kingdom and is not present in the human genome. We provide strong preliminary data supporting the concept and feasibility of this novel drug target. We have in place a strong drug discovery infrastructure for developing anti-fungal drugs, with campus leaders who are co-investigators on this grant, offering expertise in key areas and facility support, ranging from fungal and chemical biology, medicinal pharmacy, and drug lead optimization involving in vitro and in vivo animal studies. Our approach offers a powerful complimentary strategy that provides a cell based reporter system for identifying compounds that require the signaling pathway for their mode of action (aim 1), together with a pharmacophore 3-D model to find compounds that directly act on these targets in pathogenic fungi of divergent genera throughout the kingdom (aims 2 and 3). We expect that this work will ultimately lead to anti-fungal drugs that target multiple steps in this pathway, and are effective at treating a broad range of serious fungal infections in humans and perhaps plants. PUBLIC HEALTH RELEVANCE: The number of fungal infections has risen dramatically in the United States over the last 10 years, and has reached the top 10 in causes of annual mortality in part because of the lack of efficacious anti-fungal drugs. This proposal addresses that public health need by seeking to identify, characterize and capitalize on a novel drug target in pathogenic fungi for the development of effective new anti-fungal drugs.