title: Piperazinyl quinolines as chemosensitizers to increase fluconazole susceptibility of Candida albicans clinical isolates.
abstract: The effectiveness of the potent antifungal drug fluconazole is being compromised by the rise of drug-resistant fungal pathogens. While inhibition of Hsp90 or calcineurin can reverse drug resistance in Candida, such inhibitors also impair the homologous human host protein and fungal-selective chemosensitizers remain rare. The MLPCN library was screened to identify compounds that selectively reverse fluconazole resistance in a Candida albicans clinical isolate, while having no antifungal activity when administered as a single agent. A piperazinyl quinoline was identified as a new small-molecule probe (ML189) satisfying these criteria.
authors.affiliation: Chemical Biology Platform and Probe Development Center, Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Willmen
authors.initials: W
authors.lastname: Youngsaye
authors.forename: Benjamin
authors.initials: B
authors.lastname: Vincent
authors.forename: Cathy L
authors.initials: CL
authors.lastname: Hartland
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Morgan
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Buhrlage
authors.forename: Stephen
authors.initials: S
authors.lastname: Johnston
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Bittker
authors.forename: Lawrence
authors.initials: L
authors.lastname: MacPherson
authors.forename: Sivaraman
authors.initials: S
authors.lastname: Dandapani
authors.forename: Michelle
authors.initials: M
authors.lastname: Palmer
authors.forename: Luke
authors.initials: L
authors.lastname: Whitesell
authors.forename: Susan
authors.initials: S
authors.lastname: Lindquist
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Schreiber
authors.forename: Benito
authors.initials: B
authors.lastname: Munoz
mesh_terms: D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology*; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D002176:Candida albicans / Q000187:drug effects* / Q000254:growth & development / Q000302:isolation & purification; D004305:Dose-Response Relationship, Drug; D015725:Fluconazole / Q000737:chemistry / Q000494:pharmacology*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D054852:Small Molecule Libraries; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000935:Antifungal Agents; D065095:Calcineurin Inhibitors; D018841:HSP90 Heat-Shock Proteins; D011804:Quinolines; D054852:Small Molecule Libraries; D015725:Fluconazole; D019703:Calcineurin