Fish-derived cationic antimicrobial peptide piscidin 1 exerts broad-spectrum bactericidal activities against multidrug-resistant Gram-negative pathogens

The emergence and swift dissemination of multidrug-resistant (MDR) bacteria have posed a grave threat to public health. To counteract the escalating menace posed by MDR organisms, particularly mcr-1 , bla NDM-1 , or/and tet (X3/X4)-positive Gram-negative pathogens, the identification of novel antimicrobial agents or treatment strategies is imperative. Antimicrobial peptides (AMPs) have emerged as potential antibiotic candidates. In this study, we discovered that piscidin 1, a cationic AMP derived from fish, exhibits potent antibacterial activity against MDR bacteria. Safety and stability assessments revealed that this peptide demonstrates robust resistance to various physiological conditions, possesses significant biofilm inhibition capabilities, but exhibits relatively low toxicity. Mechanistic experiments showed that piscidin 1 combats MDR pathogens through multiple channels, including permeabilization of inducing outer- and inner membrane, causing membrane depolarization, dissipating the proton motive force, inhibiting efflux pumps, reducing the intracellular ATP levels and causing the accumulation of NADH and ROS. Utilizing the mouse infection model, we demonstrate piscidin 1 displayed the excellent bactericidal activity against MDR pathogens in vitro. Collectively, these findings underscore the promising potential of piscidin 1 as a candidate for combating MDR pathogens. • Piscidin 1 shows bactericidal activities against Gram-negative pathogens. • Piscidin 1 is less prone to achieve resistance and eliminates biofilms. • Piscidin 1 exerts slight cytotoxicity and high stability. • Piscidin 1 induces membrane permeabilization, suppresses the electron transport chain, and dissipate the membrane potential.