Invasive fungal infections are a leading cause of death in immunocompromised patients. While much is known about the cellular processes required for the pathogenesis of these infections, translating understanding into tangible clinical benefit has been difficult because these fungal pathogens and their hosts have similar physiology. As a result, current antifungal agents have limited clinical efficacy, are poorly fungicidal in the host, are occasionally toxic, and are increasingly ineffective due to emerging resistance. Thus, innovative antifungal targeting strategies and agents are critically needed.
Our overall hypothesis is that by applying structural biological approaches to rigorous investigations in molecular mycology, we will define critical, targetable differences between key fungal proteins controlling virulence and any existing mammalian protein counterparts. This will provide the therapeutic platform upon which we will develop fungal-specific cell signaling inhibitors that lack mammalian cross-reactivity. To accomplish our objective, we propose three synergistic, inter-related Projects supported by two scientific Cores, which will work together to achieve the following Overall Aims:
- Define fungal-specific structural differences in three cell signaling pathways. We hypothesize that structural biologic approaches (crystallography and NMR spectroscopy) will define fungal-specific differences in three cell signaling pathway targets and their inhibitors in the major fungal pathogens. These differences will distinguish our fungal targets from their mammalian counterparts and enable us to generate and screen tailored compound libraries. This customization of fungal-specific inhibitors will maximize identification of specific, novel antifungal compounds and limit cross-reactivity.
- Generate and optimize novel signaling pathway inhibitors. We hypothesize that novel signaling inhibitors identified based on knowledge from Aim 1 can be generated and then optimized to improve their presence at the target. Our structure-based approach will capitalize on the differences between fungal and mammalian systems and utilize dedicated medicinal chemistry within each Project to modify inhibitor characteristics to improve targeting and overall fungicidal activity.
- Test inhibitors in vitro and in animal models of disease. We hypothesize that our novel inhibitors from Aim 2 will possess in vitro and in vivo antifungal activity against one or more of the fungal pathogens, either as single agents or in combination with other antifungals. Active inhibitors identified in in vitro screens will be examined in animal models of invasive candidiasis, invasive aspergillosis, cryptococcosis, and mucormycosis. This in vivo evaluation is a major proposal strength and utilizes our extensive experience in both humans and animals with invasive fungal infections. These studies will provide context for continued development of novel inhibitors with significant clinical potential.