Innovative Therapeutic Targets for Fungal Keratitis

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DESCRIPTION (provided by applicant): We reported that fungal anti-oxidant pathways and iron binding molecules (siderophores) are essential for hyphal growth in the mammalian cornea (J Clin Invest 2012, PMC3708856; PLoS Pathogens 2013, PMC3534057). We also demonstrated that these pathways can be targeted using the anti-cancer drug PX-12, which inhibits the thioredoxin pathway, and by Simvastatin, which inhibits production of the Aspergillus siderophore TAFC (9, 10). In the current proposal, we also show preliminary data that inhibition of zinc transport impairs growth of Aspergillus hyphae in vitro. Studies outlined in the current proposal will examine PX-12, statins compared with other drugs that target these pathways, and which are either in routine clinical use, or which have gone through Phase I trials and shown to be non-toxic (all are commercially available). We will then combine the most effective compounds using a multi-target approach. In year 1, we will determine the most effective agents in a direct in vitro hyphal killing assay (Aim 1), in an in vitro assay designed to augment hyphal killing by human neutrophils (Aim 2), and in our established murine models of trauma induced and contact lens/biofilm induced fungal keratitis (Aim 3). In the second year, we will complete Aim 3 and based on findings in the murine models, we will examine efficacy in a new rabbit model of contact lens associated fungal keratitis. Amphotericin B or natamycin, as common therapies for fungal keratitis, will also be included, and we will examine cytotoxicity of each dru and combination. These novel approaches target essential pathways of hyphal growth in the cornea, have no anticipated systemic side effects as they are administered topically, and have considerable potential as novel therapies for this important disease.