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Identification, in vitro activity and mode of action of phosphoinositide-dependent-1 kinase inhibitors as antifungal molecules.

ABSTRACT: 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 (Pkh kinases) as part of its mode of action and support a role for Pkh 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.

SUBMITTER: Baxter BK

PROVIDER: S-EPMC3098953 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Identification, in vitro activity and mode of action of phosphoinositide-dependent-1 kinase inhibitors as antifungal molecules.

Baxter Bonnie K BK DiDone Louis L Ogu Duana D Schor Stanford S Krysan Damian J DJ

ACS chemical biology 20110222 5

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 (Pkh k ...[more]

PMID: 21294551

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