title: 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.
authors.affiliation: Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA.
authors.forename: Bonnie K
authors.initials: BK
authors.lastname: Baxter
authors.forename: Louis
authors.initials: L
authors.lastname: DiDone
authors.forename: Duana
authors.initials: D
authors.lastname: Ogu
authors.forename: Stanford
authors.initials: S
authors.lastname: Schor
authors.forename: Damian J
authors.initials: DJ
authors.lastname: Krysan
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D000935:Antifungal Agents / Q000302:isolation & purification* / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000302:isolation & purification* / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D011720:Pyrazoles / Q000302:isolation & purification / Q000494:pharmacology; D012441:Saccharomyces cerevisiae / Q000187:drug effects; D019311:Staurosporine / Q000031:analogs & derivatives / Q000302:isolation & purification / Q000494:pharmacology; D013449:Sulfonamides / Q000302:isolation & purification / Q000494:pharmacology
chemical_list: D000935:Antifungal Agents; C500894:OSU 03012; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; C054852:7-hydroxystaurosporine; D064413:3-Phosphoinositide-Dependent Protein Kinases; D017346:Protein Serine-Threonine Kinases; D019311:Staurosporine