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

Bonnie K Baxter; Louis DiDone; Duana Oga; Stanford Schor; Damian J Krysan

doi:10.1021/cb100399x

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

Journal article

Peer reviewed

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

Bonnie K Baxter, Louis DiDone, Duana Oga, Stanford Schor and Damian J Krysan

ACS chemical biology, Vol.6(5), pp.502-510

05/20/2011

DOI: 10.1021/cb100399x

PMCID: PMC3098953

PMID: 21294551

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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.

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Title: Subtitle: Identification, in vitro activity and mode of action of Phosphoinositide-dependent-1 kinase inhibitors as antifungal molecules
Creators: Bonnie K Baxter - Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642
Louis DiDone - Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642
Duana Oga - Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642
Stanford Schor - Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642
Damian J Krysan - Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642
Resource Type: Journal article
Publication Details: ACS chemical biology, Vol.6(5), pp.502-510
DOI: 10.1021/cb100399x
PMID: 21294551
PMCID: PMC3098953
NLM abbreviation: ACS Chem Biol
ISSN: 1554-8929
eISSN: 1554-8937
Language: English
Date published: 05/20/2011
Academic Unit: Microbiology and Immunology; Stead Family Department of Pediatrics; Infectious Disease (Pediatrics)
Record Identifier: 9984093374802771

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