Introduction: Staphylococcus aureus is a leading cause of nosocomial infections, particularly medical device-associated infections, causing significant morbidity and mortality among hospitalised patients.1, 2 Bacterial attachment to medical devices and biofilm formation are major drivers of failing antibiotic therapy and the persistence of chronic infections by methicillin-resistant S. aureus and methicillin-sensitive S. aureus.3 Thus, there is an urgent need for novel treatment and eradication strategies for S. aureus biofilms.
Methods: Synthetic organic chemistry was utilised to produce a new generation of nitroxide functionalised fluoroquinolone-based antibiotics with S. aureus biofilm eradication capabilities. Several novel biofilm-eradication agents and two commercially available compounds (CTEMPO and ciprofloxacin) were tested for biofilm eradication and/or dispersal in the MBECTM device, a reproducible high-throughput static biofilm formation system. Mature S. aureus biofilms were treated with serial dilutions of the specific test agent(s) and recovered cell numbers were quantified by plating for viable cell counts.
Results: Nitroxide-mediated biofilm dispersal significantly reduced S. aureus biofilm viable cell density at low concentrations (8 µM). Synergistic co-treatment with ciprofloxacin and CTEMPO (nitroxide) drastically improved the biofilm-eradication activity of ciprofloxacin (Minimal Biofilm Eradication Concentration (MBEC) of ≤4096 µM for ciprofloxacin versus ≤256 µM for ciprofloxacin plus CTEMPO). Synthetically incorporating a nitroxide into the base structure of ciprofloxacin improved its biofilm-eradication activity by 64-fold (MBEC ≤64 µM).
Conclusions: Fluoroquinolone-nitroxides are a new class of antibiotic which can disperse and eradicate S. aureus biofilms at low concentrations. Consequently, they represent a promising new therapeutic strategy which could lead to an effective treatment for S. aureus biofilm-related infections.