title: A Pipeline for Screening Small Molecules with Growth Inhibitory Activity against Burkholderia cenocepacia.
abstract: Infections with the bacteria Burkholderia cepacia complex (Bcc) are very difficult to eradicate in cystic fibrosis patients due the intrinsic resistance of Bcc to most available antibiotics and the emergence of multiple antibiotic resistant strains during antibiotic treatment. In this work, we used a whole-cell based assay to screen a diverse collection of small molecules for growth inhibitors of a relevant strain of Bcc, B. cenocepacia K56-2. The primary screen used bacterial growth in 96-well plate format and identified 206 primary actives among 30,259 compounds. From 100 compounds with no previous record of antibacterial activity secondary screening and data mining selected a total of Bce bioactives that were further analyzed. An experimental pipeline, evaluating in vitro antibacterial and antibiofilm activity, toxicity and in vivo antibacterial activity using C. elegans was used for prioritizing compounds with better chances to be further investigated as potential Bcc antibacterial drugs. This high throughput screen, along with the in vitro and in vivo analysis highlights the utility of this experimental method to quickly identify bioactives as a starting point of antibacterial drug discovery.
authors.affiliation: Department of Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Carrie
authors.initials: C
authors.lastname: Selin
authors.affiliation: Department of Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Maria S
authors.initials: MS
authors.lastname: Stietz
authors.affiliation: M. G. DeGroote Institute for Infectious Disease Research and Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada; McMaster High Throughput Screening Laboratory, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Jan E
authors.initials: JE
authors.lastname: Blanchard
authors.affiliation: M. G. DeGroote Institute for Infectious Disease Research and Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Sebastian S
authors.initials: SS
authors.lastname: Gehrke
authors.affiliation: Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Bernard
authors.affiliation: Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Dennis G
authors.initials: DG
authors.lastname: Hall
authors.affiliation: M. G. DeGroote Institute for Infectious Disease Research and Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada; McMaster High Throughput Screening Laboratory, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Brown
authors.affiliation: Department of Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Medical Microbiology and Infectious Disease, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Silvia T
authors.initials: ST
authors.lastname: Cardona
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D057508:Burkholderia cenocepacia / Q000187:drug effects* / Q000254:growth & development*; D017173:Caenorhabditis elegans / Q000187:drug effects; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005247:Feeding Behavior / Q000187:drug effects; D006461:Hemolysis / Q000187:drug effects; D057166:High-Throughput Screening Assays; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D012756:Sheep; D054852:Small Molecule Libraries / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D000900:Anti-Bacterial Agents; D054852:Small Molecule Libraries