biostudies-literatureLiu JNational Natural Science Foundation of China5https://www.ebi.ac.uk/biostudies/studies/S-EPMC12775422biostudies-literatureUnknown12(1)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 sNPJ biofilms and microbiomesIdentification of ferredoxin PA1551 as an antibacterial synergistic target for biofilm inhibitors against Pseudomonas aeruginosa.PMC127754228247378882173651Liu JYang LHu XZhou TChang YRen ALi ZZhao SJia TZhang XCai ZChen WLin JZhang CMiao ZfalseIdentification 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 s2025-01-01T00:00:00Z2025 Dec2026-06-06T13:03:53.536Z2026-05-30T03:11:34.1ZS-EPMC127754224135028110.1038/s41522-025-00871-y