Identification, in Vitro Activity and Mode of Action of Phosphoinositide-Dependent-1 Kinase Inhibitors as Antifungal Molecules

Although protein kinases have recently emerged as important drug targets, the anti-infective potential of protein kinase inhibitors has. not been developed extensively. We identified the mammalian PDK1 inhibitor KP-372-1, as a potent antifungal molecule with activity against yeast and fungal biofilms using a screening strategy for protein kinase inhibitors that block the cell wall stress response in yeast. Genetic and biochemical studies indicate that KP-372-1 inhibits fungal PDK1 orthologs (Pith kinases) as part of its mode of action and support a role for Pith kinases in eisosome assembly. Two other structurally distinct molecules that inhibit PDK1, OSU-03012 and UCN-01, also have antifungal activity. Taken together, these data indicate that fungal PDK1 orthologs are promising targets for new antifungal drug development.