The activity of a new bicyclic peptide, PLP-3, against colistin-resistant Pseudomonas aeruginosa biofilms.

New antimicrobials are urgently required to treat multidrug-resistant Pseudomonas aeruginosa infections, a hallmark of chronic respiratory diseases such as cystic fibrosis (CF), in which biofilm-associated growth contributes to antibiotic tolerance and persistence. In this study, the activity of PLP-3, an in silico designed peptidomimetic protegrin-1, was evaluated against planktonic and biofilm-associated P. aeruginosa clinical isolates from CF patients, including both colistin-susceptible (ColS) and colistin-resistant (ColR) strains. Antibacterial and antibiofilm activities were assessed by determining the minimum inhibitory concentrations (MICs of 2 mg/L and ≥4 mg/L for ColS and ColR, respectively), as well as minimum biofilm inhibitory and eradication concentrations (MBIC and MBEC of ≥32 mg/L). Under dynamic flow-cell biofilm conditions, PLP-3 exhibited rapid and uniform killing across the biofilm structure, reducing surviving biovolume to 39.6% in P. aeruginosa ColS PAO1 and 52.8% in P. aeruginosa ColR strain 41782/98 after 24 h. In contrast, colistin effectiveness was significantly compromised in resistant biofilms (89.8% surviving biovolume, p < 0.001 vs. PLP-3). Based on these in vitro results, PLP-3 may represent a promising candidate for further investigation as a potential treatment for recalcitrant colistin-resistant P. aeruginosa infections.