Broad synergistic effects of an AMP with multiple antibiotics against drug-resistant bacteria via multifaceted mechanisms.

Antimicrobial peptides (AMPs) have emerged as promising alternatives or adjuncts to antibiotics. However, most studies on AMP-antibiotic combinations focus on specific drugs or pathogens, with limited exploration of broad-spectrum synergistic effects. Herein, we demonstrate that CATHPb1, a snake-derived AMP, exhibits extensive synergistic antimicrobial activity when combined with 12 antibiotics representing six distinct mechanisms of action. Moreover, CATHPb1 shows a low potential for inducing resistance and significantly enhances anti-biofilm and anti-persister activities in combination with antibiotics. The broad-spectrum synergy of CATHPb1 can be attributed to multiple mechanisms-including specific efflux pump inhibition, ROS generation, cell wall disruption, and DNA binding-distinct from the commonly observed membrane-disrupting activity. Notably, CATHPb1 markedly enhanced antibiotic efficacy in murine models of peritonitis and bacteremia, resulting in reduced bacterial loads of multidrug-resistant bacteria, decreased inflammatory responses, and improved survival rates. These findings underscore the therapeutic potential of CATHPb1 as a versatile adjuvant for combating multidrug-resistant bacterial infections.