title: Screening the Pathogen Box for Identification of Candida albicans Biofilm Inhibitors.
abstract: 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 preformed biofilms. Interestingly, the most potent of these, compound MMV688768, displayed increased antibiofilm activity 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 antibiofilm 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.
authors: Department of Biology and The South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio, San Antonio, Texas, USA.
authors: Taissa
authors: T
authors: Vila
authors: Department of Biology and The South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio, San Antonio, Texas, USA jose.lopezribot@utsa.edu.
authors: Jose L
authors: JL
authors: Lopez-Ribot
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects* / Q000254:growth & development; D002176:Candida albicans / Q000187:drug effects* / Q000254:growth & development / Q000648:ultrastructure; D002470:Cell Survival / Q000187:drug effects; D004338:Drug Combinations; D004357:Drug Synergism; D015725:Fluconazole / Q000494:pharmacology; D056945:Hep G2 Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D010933:Plankton / Q000187:drug effects / Q000254:growth & development; D054852:Small Molecule Libraries / Q000494:pharmacology*
chemical_list: D000935:Antifungal Agents; D004338:Drug Combinations; D054852:Small Molecule Libraries; D015725:Fluconazole
keywords: Candida albicans; Pathogen Box; antifungals; biofilms; drug screening