Repurposing High-Throughput Screening Reveals Unconventional Drugs with Antimicrobial and Antibiofilm Potential Against Methicillin-Resistant Staphylococcus aureus from a Cystic Fibrosis Patient

Background/Objectives: Antibiotic therapy faces challenges due to rising acquired and biofilm-related antibiotic resistance rates. High resistance levels to commonly used antibiotics have been observed in methicillin-resistant Staphylococcus aureus (MRSA) strains among cystic fibrosis (CF) patients, indicating an urgent need for new antibacterial agents. For the first time, this study aimed to identify potential novel therapeutics with antibacterial and antibiofilm activities against an MRSA CF strain by screening a drug repurposing library. Methods/Results: Among the 3,386 compounds, high throughput screening identified 2,439 (72%), 654 (19.3%), and 426 (12.6%) drugs active against planktonic cells, biofilm formation, and preformed biofilm, respectively, although at different extents. The most active hits were 193 (5.7%) against planktonic cells, causing a 100% growth inhibition; 5 (0.14%) with excellent activity against biofilm formation (i.e., reduction ≥ 90%); and 4 showing high activity (i.e., 60% ≤ biofilm reduction < 90%) against preformed biofilms. The potential hits belonged to several primary research areas, with “cancer” as the most prevalent. After performing a literature review to identify other, already published, biological properties that could be relevant to the CF lung environment (i.e., activity against other CF pathogens, anti-inflammatory and anti-virulence potential), the most interesting hits were: 5-(N,N-Hexamethylene)-amiloride (diuretic), Toremifene (anticancer), and Zafirlukast (antiasthmatic), Fenretide (anticancer), and Montelukast (antiasthmatic) against planktonic S. aureus cells; Hemin against biofilm formation; and Heparin, Clemastine (antihistaminic), and Bromfenac (nonsteroidal anti-inflammatory) against established biofilms. Conclusions: These findings warrant further in vitro and in vivo studies to confirm the potential of repurposing these compounds for managing lung infections caused by S. aureus in CF patients.