Xu Bocheng, Wang Lin, Yang Chen, Yan Rong, Zhang Pan, Jin Mingliang, Du Huahua, Wang Yizhen
National Engineering Research Center for Green Feed and Healthy Breeding, Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Institute of Feed Science, Zhejiang University, Hangzhou 310058, China.
Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310007, China.
J Adv Res. 2025 Jan;67:301-315. doi: 10.1016/j.jare.2024.01.023. Epub 2024 Jan 22.
The design of precision antimicrobials aims to personalize the treatment of drug-resistant bacterial infections and avoid host microbiota dysbiosis.
This study aimed to propose an efficient de novo design strategy to obtain specifically targeted antimicrobial peptides (STAMPs) against methicillin-resistant Staphylococcus aureus (MRSA).
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.
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 distribution and efficacy, and immunomodulatory activity in vivo. Furthermore, a bacterial-entrapping peptide (BEP, SP5) modified from P18, self-assembled into nanonetworks and rapidly entrapped MRSA. SP5 synergized with P18E6 to enhance antibacterial activity in vitro and reduced systemic MRSA infections.
This strategy may aid in the design of STAMPs against drug-resistant strains, and BEPs can serve as powerful STAMP adjuvants.
精准抗菌药物的设计旨在实现耐药细菌感染的个性化治疗，并避免宿主微生物群失调。
本研究旨在提出一种高效的从头设计策略，以获得针对耐甲氧西林金黄色葡萄球菌（MRSA）的特异性靶向抗菌肽（STAMP）。
我们评估了三种旨在提高抗菌肽（AMP）对MRSA选择性的策略，并主要采用了一种先进的杂合肽策略。首先，我们提出了一种遍历设计来生成序列，并构建机器学习模型来预测未知肽的抗金黄色葡萄球菌活性水平。随后，预测有六种肽具有高活性，其中选择了一种广谱AMP（P18）。最后，使用来自噬菌体展示文库的两种靶向肽或溶葡萄球菌素赋予P18特异性抗金黄色葡萄球菌活性。基于其体外和体内活性，从杂合肽中进一步筛选出STAMP。
一种先进的杂合肽策略可以增强广谱AMP的特异性和靶向性。在评估的25种肽中，10种通过了体外测试，两种含有一种细菌捕获肽（BEP）和一种STAMP的肽通过了体内测试。先导STAMP（P18E6）破坏了MRSA的细胞壁和细胞膜，消除了已形成的生物膜，并在体内表现出理想的生物相容性、全身分布和疗效以及免疫调节活性。此外，从P18修饰而来的一种细菌捕获肽（BEP，SP5）自组装成纳米网络并迅速捕获MRSA。SP5与P18E6协同作用以增强体外抗菌活性并减少全身MRSA感染。
该策略可能有助于设计针对耐药菌株的STAMP，并且BEP可作为强大的STAMP佐剂。
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