One of the most important clinical obstacles in cystic fibrosis (CF) is antibiotic treatment failure due to biofilms produced by Pseudomonas aeruginosa. The ability of this pathogen to survive eradication by tobramycin and pathoadapt into a hyper-biofilm state leading to chronic infections is key to its success. Retrospective studies have demonstrated that preventing this pathoadaptation by improving eradication is essential to extend the lives of CF patients. To identify adjuvants that enhance tobramycin eradication of P. aeruginosa, we performed a high-throughput screen of 6,080 compounds from four drug repurposing libraries. We identified that the Food and Drug Administration (FDA) approved compound, triclosan, combined with tobramycin resulted in a 100-fold reduction of viable cells within biofilms at six hours, but neither compound alone had significant antimicrobial activity against biofilms. This synergistic treatment significantly accelerated killing of biofilms compared to tobramycin treatment alone, and the combination was effective against 6/7 CF clinical isolates compared to tobramycin treatment alone including a tobramycin resistant strain. Further, triclosan and tobramycin killed persister cells, causing a 100-fold reduction by 8-hrs and complete eradication by 24-hrs. Triclosan also enhances tobramycin killing of multiple Burkholderia cenocepacia and Staphylococcus aureus clinical isolates grown as biofilms. Additionally, triclosan synergized with other aminoglycosides such as gentamicin or streptomycin. Triclosan is a well-tolerated aminoglycoside adjuvant shown to be safe for human use that could improve treatment of biofilm-based infections.
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