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dc.contributor.author LaFayette, SL
dc.contributor.author Collins, C
dc.contributor.author Zaas, AK
dc.contributor.author Schell, WA
dc.contributor.author Betancourt-Quiroz, M
dc.contributor.author Gunatilaka, AA
dc.contributor.author Perfect, JR
dc.contributor.author Cowen, LE
dc.coverage.spatial United States
dc.date.accessioned 2011-06-21T17:32:23Z
dc.date.issued 2010-08-26
dc.identifier http://www.ncbi.nlm.nih.gov/pubmed/20865172
dc.identifier.citation PLoS Pathog, 2010, 6 (8), pp. e1001069 - ?
dc.identifier.uri http://hdl.handle.net/10161/4605
dc.description.abstract Fungal pathogens exploit diverse mechanisms to survive exposure to antifungal drugs. This poses concern given the limited number of clinically useful antifungals and the growing population of immunocompromised individuals vulnerable to life-threatening fungal infection. To identify molecules that abrogate resistance to the most widely deployed class of antifungals, the azoles, we conducted a screen of 1,280 pharmacologically active compounds. Three out of seven hits that abolished azole resistance of a resistant mutant of the model yeast Saccharomyces cerevisiae and a clinical isolate of the leading human fungal pathogen Candida albicans were inhibitors of protein kinase C (PKC), which regulates cell wall integrity during growth, morphogenesis, and response to cell wall stress. Pharmacological or genetic impairment of Pkc1 conferred hypersensitivity to multiple drugs that target synthesis of the key cell membrane sterol ergosterol, including azoles, allylamines, and morpholines. Pkc1 enabled survival of cell membrane stress at least in part via the mitogen activated protein kinase (MAPK) cascade in both species, though through distinct downstream effectors. Strikingly, inhibition of Pkc1 phenocopied inhibition of the molecular chaperone Hsp90 or its client protein calcineurin. PKC signaling was required for calcineurin activation in response to drug exposure in S. cerevisiae. In contrast, Pkc1 and calcineurin independently regulate drug resistance via a common target in C. albicans. We identified an additional level of regulatory control in the C. albicans circuitry linking PKC signaling, Hsp90, and calcineurin as genetic reduction of Hsp90 led to depletion of the terminal MAPK, Mkc1. Deletion of C. albicans PKC1 rendered fungistatic ergosterol biosynthesis inhibitors fungicidal and attenuated virulence in a murine model of systemic candidiasis. This work establishes a new role for PKC signaling in drug resistance, novel circuitry through which Hsp90 regulates drug resistance, and that targeting stress response signaling provides a promising strategy for treating life-threatening fungal infections.
dc.format.extent e1001069 - ?
dc.language ENG
dc.language.iso en_US en_US
dc.relation.ispartof PLoS Pathog
dc.relation.isversionof 10.1371/journal.ppat.1001069
dc.subject Animals
dc.subject Antifungal Agents
dc.subject Calcineurin
dc.subject Candida albicans
dc.subject Drug Resistance, Fungal
dc.subject Fungal Proteins
dc.subject HSP90 Heat-Shock Proteins
dc.subject Immunoblotting
dc.subject Mice
dc.subject Microbial Sensitivity Tests
dc.subject Mitogen-Activated Protein Kinases
dc.subject Protein Kinase C
dc.subject Reverse Transcriptase Polymerase Chain Reaction
dc.subject Saccharomyces cerevisiae
dc.subject Signal Transduction
dc.title PKC signaling regulates drug resistance of the fungal pathogen Candida albicans via circuitry comprised of Mkc1, calcineurin, and Hsp90.
dc.title.alternative en_US
dc.type Journal Article
dc.description.version Version of Record en_US
duke.date.pubdate 2010-8-0 en_US
duke.description.endpage e1001069 en_US
duke.description.issue 8 en_US
duke.description.startpage e1001069 en_US
duke.description.volume 6 en_US
dc.relation.journal Plos Pathogens en_US
pubs.author-url http://www.ncbi.nlm.nih.gov/pubmed/20865172
pubs.issue 8
pubs.organisational-group /Duke
pubs.organisational-group /Duke/School of Medicine
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments/Molecular Genetics and Microbiology
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Medicine
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Medicine/Medicine, Infectious Diseases
pubs.publication-status Published online
pubs.volume 6
dc.identifier.eissn 1553-7374

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