Specifically targeted antimicrobial peptides synergize with bacterial-entrapping peptide against systemic MRSA infections

作者：Bocheng Xu, Lin Wang, Chen Yang, Rong Yan, Pan Zhang, Mingliang Jin, Huahua Du, Yizhen Wang · 发表于：Journal of Advanced Research · 年份：2024 · DOI：10.1016/j.jare.2024.01.023 · 被引用次数：36 · 研究领域：Antimicrobial Peptides and Activities、Antimicrobial agents and applications、Biochemical and Structural Characterization

INTRODUCTION: The design of precision antimicrobials aims to personalize the treatment of drug-resistant bacterial infections and avoid host microbiota dysbiosis. OBJECTIVES: This study aimed to propose an efficient de novo design strategy to obtain specifically targeted antimicrobial peptides (STAMPs) against methicillin-resistant Staphylococcus aureus (MRSA). METHODS: We evaluated three strategies designed to increase the selectivity of antimicrobial peptides (AMPs) for MRSA and mainly adopted an advanced hybrid peptide strategy. First, we proposed a traversal design to generate sequences, and constructed machine learning models to predict the anti-S. aureus activity levels of unknown peptides. Subsequently, six peptides were predicted to have high activity, among which, a broad-spectrum AMP (P18) was selected. Finally, the two targeting peptides from phage display libraries or lysostaphin were used to confer specific anti-S. aureus activity to P18. STAMPs were further screened out from hybrid peptides based on their in vitro and in vivo activities. RESULTS: An advanced hybrid peptide strategy can enhance the specific and targeted properties of broad-spectrum AMPs. Among 25 assessed peptides, 10 passed in vitro tests, and two peptides containing one bacterial-entrapping peptide (BEP) and one STAMP passed an in vivo test. The lead STAMP (P18E6) disrupted MRSA cell walls and membranes, eliminated established biofilms, and exhibited desirable biocompatibility, systemic distrib...