Development of Novel Antimicrobial Peptides and Their Engineering into Nanoparticles to Improve Performance

Abstract Antimicrobial peptides (AMPs) are promising alternatives to antibiotics, but discovering potent, low-toxicity candidates and improving their delivery remain challenging. In this study, novel AMPs were identified by constructing and screening a synthetic random peptide library using a bacterial surface display system. Rational design generated derivative peptides, among which WP-4 and WP-6 showed high antimicrobial activity, good biocompatibility, rapid bactericidal effects, and low propensity for resistance development. WP-6 also showed good in vivo therapeutic potency in a murine Escherichia coli systemic infection model. Mechanistic studies indicated that WP-4 and WP-6 target bacterial cell membranes, disrupt the proton motive force, and induce excessive reactive oxygen species accumulation. To further improve their activity and in vivo performance, WP-4 and WP-6 were encapsulated within zeolitic imidazolate framework-8, yielding improved antimicrobial activity and proteolytic resistance. These nanoparticles exhibited superior therapeutic efficacy in a Streptococcus suis-induced arthritis model. Our study identified potent AMPs with promising therapeutic potential.