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.
Shuai-Yang Wang, S.-S. Wang, Xiu-Jian Liu et al.· Journal of Medicinal Chemist...· 0 citations
Shiga toxin-producing Escherichia coli (STEC) is a major food-borne pathogen with limited treatment options. Targeting Shiga toxin (Stx) represents a promising therapeutic strategy. Using artificial intelligence (AI)-assisted de novo protein design combined with bacterial surface display screening, pull-down assays, and biolayer interferometry, we identified protein binders against the Stx2a B subunit (Stx2aB), among which Binder506 exhibited high affinity. Structural modeling predicted a three-α-helix fold, consistent with circular dichroism analysis, while differential scanning fluorimetry revealed high thermostability. Importantly, Binder506 demonstrated potent Stx2a-neutralizing activity with minimal intrinsic cytotoxicity in Vero cells. Size-exclusion chromatography and coimmunoprecipitation showed that Binder506 did not disrupt Stx2a holotoxin integrity. Instead, cellular binding and internalization assays demonstrated that Binder506 inhibited Stx2a attachment to and uptake by Vero cells. Collectively, these findings demonstrate the potential of AI-assisted de novo protein design for generating effective Stx-neutralizing proteins and establish a promising framework for the development of novel therapeutics.
Xiang-Lin Zhao, Xiao-Tang Feng, Huai-Xia Li et al.· Journal of Agricultural and...· 0 citations
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