Quinacrine inhibits Candida albicans growth and filamentation at neutral pH.

Quinacrine inhibits Candida albicans growth and filamentation at neutral pH.

Antimicrob Agents Chemother. 2014 Oct 6;

Authors: Kulkarny VV, Chavez-Dozal A, Rane HS, Jahng M, Bernardo SM, Parra KJ, Lee SA

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 could identify agents 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 (4-2048μg/ml) and assessed using the 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 inhibition of filamentation, effects on endocytosis, and pH-dependent activity. High-dose QNC was effective for 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 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 anti-biofilm activity likely occurs via several independent mechanisms: vacuolar alkalinization, inhibition of endocytosis, and impaired filamentation. Further investigation of QNC for treatment and prevention of biofilm-related Candida CR-BSI is warranted.

PMID: 25288082 [PubMed - as supplied by publisher]