The study shows that the natural antimicrobial peptide LL‑37, which can kill Pseudomonas aeruginosa in lab tests, becomes much less effective in the acidic, lactate‑rich airways of bronchiectasis patients because the bacteria release tiny vesicles that boost a chemical (HHQ) that blocks LL‑37 from sticking to the bacteria.

<i>Pseudomonas aeruginosa</i> is the predominant pathogen causing chronic infection in the airway of patients with bronchiectasis (BE), a chronic respiratory disease with high prevalence worldwide. Environmental factors are vital for bacterial successful colonization. Here, with sputa and bronchoalveolar lavage fluids, we determined that the concentration of airway antimicrobial peptide LL-37 and lactate was elevated in BE patients, especially in those infected with <i>P. aeruginosa</i>. The in vitro antibacterial assay revealed the bactericidal activity of LL-37 against the clinical <i>P. aeruginosa</i> isolates, which were dampened in the acidic condition. <i>P. aeruginosa</i> production of outer membrane vesicles (OMVs) enhanced in the lactate-adjusted acidic condition. Transcriptomic analysis suggested that OMVs induce the hyperproduction of the chemical compound 2-heptyl-4-quinolone (HHQ) in the bacterial population, which was verified by high-performance liquid chromatography. The positively charged HHQ interfered with the binding of LL-37 to bacterial cell membrane, potentiating the <i>P. aeruginosa</i> resistance to LL-37. To our knowledge, this is a new resistance mechanism of <i>P. aeruginosa</i> against antimicrobial peptides and may provide theoretical support for the development of new antibacterial therapies.