Engineering β-amino acid antimicrobial peptides with enhanced stability and potential efficacy against gram-negative...

Antibiotics revolutionized bacterial infection treatment, but misuse has led to the rise of antimicrobial resistance, which threatens global health. In this study, a series of new antimicrobial peptides containing β-amino acid were developed, and some of them showed potent antibacterial activity and minimal hemolytic toxicity. Amongst AP-12 had a highly effective against the gram-negative bacteria and showed enhanced stability in simulated physiological conditions, including in the presence of protease, serum, and high-salt levels. Importantly, AP-12 had a low tendency for the bacteria to develop resistance and was more effective against multidrug-resistant bacteria clinical isolates than the traditional antibiotics like gentamicin and imipenem. Mechanistic studies revealed that AP-12 can bind to the lipopolysaccharides and kills bacteria by disrupting the inner and outer membrane integrity, depolarizing the membranes in a concentration-dependent manner, and producing reactive oxygen species. In vivo, AP-12 reduced the bacterial loads in major organs or tissues and promoted tissue healing in systemic, pneumonia, and wound infection models. It also displayed a better safety profile compared to polymyxin B. Our findings highlight that the new modifying antimicrobial peptides with β-amino acids can greatly improve their stability and antibacterial potency. And the results show that AP-12 is a promising candidate for combating drug-resistant gram-negative bacterial infections.