A 4-Arm polyethylene-glycol-based multivalent galactoside disrupts Pseudomonas aeruginosa biofilm and restores antibiotic susceptibility.

The formation of Pseudomonas aeruginosa (P. aeruginosa) biofilm significantly enhances bacterial resistance to antimicrobial agents and escape from the host immune system, making the treatment of related infections considerably more challenging. As a potential approach for anti-biofilm strategies, the inhibition of lectins often relies on multivalent interactions to enhance binding affinity between the inhibitor and its target. In this study, targeting the P. aeruginosa lectin LecA, we constructed a polyethylene glycol-based multivalent galactoside, termed 4-Arm-PEG-Gal, by modifying the termini of 4-Arm-PEG with galactosides specific to LecA. The results indicate that 4-Arm-PEG-Gal significantly disrupts mature biofilm and is specifically recognized by the lectin LecA. Compared to the use of antibiotics alone, the combination of 4-Arm-PEG-Gal and TOB reduces antibiotic usage by 75% and additionally eradicates 73% of the bacteria within the biofilm. Furthermore, in a model of chronic lung infection, the combination of 4-Arm-PEG-Gal and TOB cleared all bacteria from the lungs, significantly reduced the secretion of TNF-α and IL-6 in the lungs, and effectively ameliorated lung damage caused by bacterial infection.