Antimicrobial activity of the BAM complex-targeting peptides against multidrug-resistant gram-negative bacteria

Multidrug-resistant (MDR) Gram-negative bacteria represent a notable public health threat, necessitating the urgent development of new antimicrobial agents. The {beta}-barrel assembly machinery (BAM) complex, crucial for the biogenesis of outer membrane proteins in Gram-negative bacteria, emerges as a promising target for drug development. The BAM complex comprises five proteins (BamA-E), and its functionality might be disrupted by peptides targeting the BamA and BamB interface. We synthesized the peptide LTLR, located in the BamB interaction region with BamA in Pseudomonas aeruginosa, and assessed its anti-P. aeruginosa activity. This peptide demonstrated potential in enhancing antibiotic efficacy against P. aeruginosa. Conversely, LRTL, a scrambled version of LTLR, lacked activity, underscoring the importance of specific target site binding for the peptides adjuvant effect. Subsequently, we tested the hypothesis that peptide dimerization enhances its effectiveness. A dimeric peptide, composed of two LTLR sequences, was tested and found to possess bactericidal activity against P. aeruginosa, an outcome not observed with the monomeric form. Importantly, this dimeric peptide also showed bactericidal activity against MDR P. aeruginosa strains. In summary, our findings offer a foundation for developing novel antimicrobial agents against MDR Gram-negative bacteria. IMPORTANCEThis work demonstrates that (1) the {beta}-barrel assembly machinery (BAM) complex-targeting peptides can exhibit antimicrobial activity and that (2) the dimeric forms of these peptides exhibit bactericidal activity against multidrug-resistant (MDR) strains of P. aeruginosa and A. baumannii.