Organic Acids and Their Salts Potentiate the Activity of Selected Antibiotics against Pseudomonas aeruginosa Biofilms Grown in a Synthetic Cystic Fibrosis Sputum Medium.

The failure of antibiotic therapy in respiratory tract infections in cystic fibrosis is partly due to the high tolerance observed in Pseudomonas aeruginosa biofilms. This tolerance is mediated by changes in bacterial metabolism linked to growth in biofilms, opening up potential avenues for novel treatment approaches based on modulating metabolism. The goal of the present study was to identify carbon sources that increase the inhibiting and/or eradicating activity of tobramycin, ciprofloxacin, and ceftazidime against P. aeruginosa PAO1 biofilms grown in a synthetic cystic fibrosis sputum medium (SCFM2) and to elucidate their mode of action. After screening 69 carbon sources, several combinations of antibiotics + carbon sources that showed markedly higher anti-biofilm activity than antibiotics alone were identified. d,l-malic acid and sodium acetate could potentiate both biofilm inhibiting and eradicating activity of ciprofloxacin and ceftazidime, respectively, while citric acid could only potentiate biofilm inhibitory activity of tobramycin. The mechanisms underlying the increased biofilm eradicating activity of combinations ciprofloxacin/d,l-malic acid and ceftazidime/sodium acetate are similar but not identical. Potentiation of ceftazidime activity by sodium acetate was linked to increased metabolic activity, a functional TCA cycle, increased ROS production, and high intracellular pH, whereas the latter was not required for d,l-malic acid potentiation of ciprofloxacin. Finally, our results indicate that the potentiation of antibiotic activity by carbon sources is strain dependent.