Identification of ferredoxin PA1551 in the bacterial iron uptake pathway and exploration of its antibacterial synergistic as target for biofilm inhibitors against Pseudomonas aeruginosa infection

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(1 H )-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 200-fold) and ciprofloxacin (CIP, by 1000-fold) compared to single-dose antibiotic treatments in a mouse model of Pseudomonas aeruginosa 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.