Candida albicans remains the main causative agent of candidiasis, one of the most frequent nosocomial infections, with unacceptably high mortality rates. Biofilm formation is a major risk factor for invasive candidiasis as Candida biofilms display high level resistance to most antifungal agents. In this work we have screened the Pathogen Box® chemical library (Medicines for Malaria Venture - MMV, Switzerland) in search for inhibitors of C. albicans biofilm formation. Our initial screen identified seven hits, and additional dose-response assays confirmed the biofilm-inhibitory activity of six of these small molecules. Three compounds, MMV688768, MMV687273 and MMV687807, were also able to reduce the metabolic activity of cells within pre-formed biofilms. Interestingly, the most potent of these, compound MMV688768, displayed increased anti-biofilm activity as compared to its activity against planktonic cultures, indicating that it may affect processes with a predominant role during the biofilm mode of growth. This compound demonstrated a high selectivity index when its anti-biofilm activity was compared with its toxicity in liver hepatocellular cells. In vitro combination assays showed a synergistic interaction between compound MMV688768 and fluconazole against preformed biofilms. Overall our results indicate that this compound may constitute a potential candidate for further clinical development.
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