Validation of a Cystic Fibrosis Co-Culture Model for the Identification of Dual Acting Compounds with Antibiotic and Antibiotic Adjuvant Properties.

Infections in the lungs of cystic fibrosis (CF) patients are often polymicrobial in nature, typically comprising Pseudomonas aeruginosa and Staphylococcus aureus. Compounds that act as an antimicrobial agent against one of these pathogens, and as an antibiotic adjuvant against the other, could provide a valuable approach to treating such infections, however a model that mimics the unique environment found with the CF lung is required for the identification and characterization of such molecules. To address this, we employed a S. aureus/P. aeruginosa coculture screening model in synthetic sputum, and identified compounds from our in-house library that simultaneously have potent anti-S. aureus activity, and potentiate colistin against colistin-resistant P. aeruginosa. The two lead compounds, 12F1 and 12G9, control growth of both species when dosed alongside sub-inhibitory concentrations of colistin, highlighting the potential of using a single molecule as both an antibiotic and antibiotic adjuvant to target multiple species in polymicrobial infections, as well as the importance of conducting activity screens in clinically relevant media.