An effective approach to obtain functional poly-β-peptides for combating drug-resistant bacterial infections

The high mortality of drug-resistant bacterial infections, especially those caused by multidrug-resistant Gram-negative pathogens, highlights an urgent demand for promising antimicrobial strategies. Host defense peptide (HDP)-mimicking poly-β-peptides have demonstrated significant potential in combating drug-resistant bacterial infections, with their antimicrobial activity closely dependent on their side-chain structures. However, the restricted structural diversity of poly-β-peptides necessitates efficient synthetic methods to expand their diversity, particularly positively charged side-chain structures. This study presents a water-tolerant approach that facilitates the controllable synthesis of poly-β-peptides with different chain lengths and structurally diverse side chains, including primary amines, tertiary amines, as well as alkyl, aryl, and methoxy groups. This approach serves as an HDP-mimicking discovery platform to obtain the optimal poly-β-peptide, AOc_0.8HNL_0.2, which exhibits broad-spectrum antibacterial activity and high selectivity against drug-resistant bacteria. The antibacterial mechanism studies reveal that AOc_0.8HNL_0.2 disrupts the membrane of Gram-negative bacteria. In vivo evaluations substantiate the therapeutic potential of AOc_0.8HNL_0.2 in treating drug-resistant bacterial infections with no observable toxicity. This study underscores the potential of this convenient synthetic strategy as a promising platform for developing antimicrobial poly-β-peptides to combat the growing threat of drug-resistant bacterial infections.