Identification of ferredoxin PA1551 as an antibacterial synergistic target for biofilm inhibitors against Pseudomonas aeruginosa

Addressing antibiotic-resistant bacterial biofilm infections without promoting drug resistance is a pressing challenge. Pseudomonas aeruginosa is well known for causing biofilm-associated drug-resistant infections that often lead to treatment failure. In this study, we identified a previously uncharacterized membrane protein ferredoxin encoded by PA1551 using photoaffinity-based biomimetic probes based on our previous dual-acting antibiofilm compound 2-(heptanamido)methyl 3-hydroxy-1,6-dimethylpyridin-4(1H)-one (10d). The precision-targeted ferredoxin PA1551 exhibited excellent effectiveness in various model systems, suppressing bacterial biofilm and virulence, and enhancing the antibacterial effects of tobramycin (Tob, by about 200-fold) and ciprofloxacin (CIP, by 1000-fold) compared to single-dose antibiotic treatments in a mouse model of Pseudomonas aeruginosa wound infection. These results indicate that ferredoxin PA1551 can be used as target to design new antibiofilm drugs for the treatment of Pseudomonas aeruginosa infections, particularly challenging bacterial biofilms.