title: Quinacrine inhibits Candida albicans growth and filamentation at neutral pH.
abstract: Candida albicans is a common cause of catheter-related bloodstream infections (CR-BSI), in part due to its strong propensity to form biofilms. Drug repurposing is an approach that might identify agents that are able to overcome antifungal drug resistance within biofilms. Quinacrine (QNC) is clinically active against the eukaryotic protozoan parasites Plasmodium and Giardia. We sought to investigate the antifungal activity of QNC against C. albicans biofilms. C. albicans biofilms were incubated with QNC at serially increasing concentrations (4 to 2,048 μg/ml) and assessed using a 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) assay in a static microplate model. Combinations of QNC and standard antifungals were assayed using biofilm checkerboard analyses. To define a mechanism of action, QNC was assessed for the inhibition of filamentation, effects on endocytosis, and pH-dependent activity. High-dose QNC was effective for the prevention and treatment of C. albicans biofilms in vitro. QNC with fluconazole had no interaction, while the combination of QNC and either caspofungin or amphotericin B demonstrated synergy. QNC was most active against planktonic growth at alkaline pH. QNC dramatically inhibited filamentation. QNC accumulated within vacuoles as expected and caused defects in endocytosis. A tetracycline-regulated VMA3 mutant lacking vacuolar ATPase (V-ATPase) function demonstrated increased susceptibility to QNC. These experiments indicate that QNC is active against C. albicans growth in a pH-dependent manner. Although QNC activity is not biofilm specific, QNC is effective in the prevention and treatment of biofilms. QNC antibiofilm activity likely occurs via several independent mechanisms: vacuolar alkalinization, inhibition of endocytosis, and impaired filamentation. Further investigation of QNC for the treatment and prevention of biofilm-related Candida CR-BSI is warranted.
authors.affiliation: Section of Infectious Diseases, New Mexico Veterans Health Care System, Albuquerque, New Mexico, USA.
authors.forename: Vibhati V
authors.initials: VV
authors.lastname: Kulkarny
authors.affiliation: Section of Infectious Diseases, New Mexico Veterans Health Care System, Albuquerque, New Mexico, USA Division of Infectious Diseases, University of New Mexico Health Science Center, Albuquerque, New Mexico, USA.
authors.forename: Alba
authors.initials: A
authors.lastname: Chavez-Dozal
authors.affiliation: Section of Infectious Diseases, New Mexico Veterans Health Care System, Albuquerque, New Mexico, USA.
authors.forename: Hallie S
authors.initials: HS
authors.lastname: Rane
authors.affiliation: Section of Infectious Diseases, New Mexico Veterans Health Care System, Albuquerque, New Mexico, USA.
authors.forename: Maximillian
authors.initials: M
authors.lastname: Jahng
authors.affiliation: Section of Infectious Diseases, New Mexico Veterans Health Care System, Albuquerque, New Mexico, USA.
authors.forename: Stella M
authors.initials: SM
authors.lastname: Bernardo
authors.affiliation: Department of Biochemistry, University of New Mexico Health Science Center, Albuquerque, New Mexico, USA.
authors.forename: Karlett J
authors.initials: KJ
authors.lastname: Parra
authors.affiliation: Section of Infectious Diseases, New Mexico Veterans Health Care System, Albuquerque, New Mexico, USA Division of Infectious Diseases, University of New Mexico Health Science Center, Albuquerque, New Mexico, USA samalee@salud.unm.edu.
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Lee
mesh_terms: D000666:Amphotericin B / Q000494:pharmacology*; D000935:Antifungal Agents / Q000494:pharmacology*; D000981:Antiprotozoal Agents / Q000494:pharmacology; D018441:Biofilms / Q000187:drug effects* / Q000254:growth & development; D002176:Candida albicans / Q000187:drug effects* / Q000254:growth & development; D000077336:Caspofungin; D004338:Drug Combinations; D058492:Drug Repositioning; D025141:Drug Resistance, Fungal; D004357:Drug Synergism; D054714:Echinocandins / Q000494:pharmacology*; D004705:Endocytosis / Q000187:drug effects; D015725:Fluconazole / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D025301:Hyphae / Q000187:drug effects / Q000254:growth & development; D055666:Lipopeptides; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D010933:Plankton / Q000187:drug effects / Q000254:growth & development; D011796:Quinacrine / Q000494:pharmacology*
chemical_list: D000935:Antifungal Agents; D000981:Antiprotozoal Agents; D004338:Drug Combinations; D054714:Echinocandins; D055666:Lipopeptides; D000666:Amphotericin B; D015725:Fluconazole; D000077336:Caspofungin; D011796:Quinacrine