title: Redox-active compounds with a history of human use: antistaphylococcal action and potential for repurposing as topical antibiofilm agents.
abstract: OBJECTIVE
  To investigate the antistaphylococcal/antibiofilm activity and mode of action (MOA) of a panel of redox-active (RA) compounds with a history of human use and to provide a preliminary preclinical assessment of their potential for topical treatment of staphylococcal infections, including those involving a biofilm component.
  
  
  METHODS
  Antistaphylococcal activity was evaluated by broth microdilution and by time-kill studies with growing and slow- or non-growing cells. The antibiofilm activity of RA compounds, alone and in combination with established antibacterial agents, was assessed using the Calgary Biofilm Device. Established assays were used to examine the membrane-perturbing effects of RA compounds, to measure penetration into biofilms and physical disruption of biofilms and to assess resistance potential. A living skin equivalent model was used to assess the effects of RA compounds on human skin.
  
  
  RESULTS
  All 15 RA compounds tested displayed antistaphylococcal activity against planktonic cultures (MIC 0.25-128 mg/L) and 7 eradicated staphylococcal biofilms (minimum biofilm eradication concentration 4-256 mg/L). The MOA of all compounds involved perturbation of the bacterial membrane, whilst selected compounds with antibiofilm activity caused destructuring of the biofilm matrix. The two most promising agents [celastrol and nordihydroguaiaretic acid (NDGA)] in respect of antibacterial potency and selective toxicity against bacterial membranes acted synergistically with gentamicin against biofilms, did not damage artificial skin following topical application and exhibited low resistance potential.
  
  
  CONCLUSIONS
  In contrast to established antibacterial drugs, some RA compounds are capable of eradicating staphylococcal biofilms. Of these, celastrol and NDGA represent particularly attractive candidates for development as topical antistaphylococcal biofilm treatments.
authors.affiliation: Antimicrobial Research Centre and School of Molecular and Cellular Biology, University of Leeds, Leeds, UK.
authors.forename: N
authors.initials: N
authors.lastname: Ooi
authors.affiliation: Harrogate and District NHS Foundation Trust, Harrogate, UK.
authors.forename: E A
authors.initials: EA
authors.lastname: Eady
authors.affiliation: Antimicrobial Research Centre and School of Molecular and Cellular Biology, University of Leeds, Leeds, UK.
authors.forename: J H
authors.initials: JH
authors.lastname: Cove
authors.affiliation: Antimicrobial Research Centre and School of Molecular and Cellular Biology, University of Leeds, Leeds, UK a.j.oneill@leeds.ac.uk.
authors.forename: A J
authors.initials: AJ
authors.lastname: O'Neill
mesh_terms: D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000891:Anti-Infective Agents, Local / Q000008:administration & dosage / Q000494:pharmacology; D018441:Biofilms / Q000187:drug effects; D024881:Drug Resistance, Bacterial; D006801:Humans; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D009154:Mutation; D010084:Oxidation-Reduction / Q000187:drug effects*; D013210:Staphylococcus / Q000187:drug effects* / Q000502:physiology*; D013211:Staphylococcus aureus / Q000187:drug effects / Q000502:physiology; D013212:Staphylococcus epidermidis / Q000187:drug effects / Q000502:physiology
chemical_list: D000900:Anti-Bacterial Agents; D000891:Anti-Infective Agents, Local
keywords: Staphylococcus aureus; Staphylococcus epidermidis; antibacterial; biofilm; mode of action