Discovery of a novel sea snake antimicrobial peptide Hydrostatin-AMP3 with dual-mechanism against multidrug-resistant Klebsiella pneumoniae.

Klebsiella pneumoniae (K. pneumoniae) has ranked in the top three pathogens responsible for bacteria-related mortal infections. The emergence of multi-drug resistant (MDR) K. pneumoniae strains highlights an urgent need for novel antimicrobial agents. In this study, a series of antimicrobial peptides (AMPs) were screened based on gene annotation and sequence profiling via high-quality whole genome maps of sea snakes Hydrophis curtus and Hydrophis cyanocinctus. The most potent Hydrostatin-AMP3 showed efficient antimicrobial capacity against a panel of pathogenic bacteria, particularly MDR K. pneumoniae strains. Moreover, Hydrostatin-AMP3 exhibited remarkable efficacy in infection models of MDR K. pneumoniae, while demonstrating favourable profiles in safety and resistance development both in vitro and in vivo studies. Mechanistically, Hydrostatin-AMP3 exerted a bactericidal effect through a unique dual-mechanism: bacterial membrane disruption and DNA-targeting. Overall, this study presented Hydrostatin-AMP3 as the potential antimicrobial candidate for the treatment of MDR K. pneumoniae infection.