金黄色葡萄球菌（金葡菌）是常见致病菌，其感染的治疗主要依靠抗生素。但抗生素是广谱抗菌药，易导致人体菌群失调，副作用严重。一种高效特异性的替代方法是使用溶葡球菌酶（Lst）。然而在真实使用环境如血液、小肠中，金葡菌耐受Lst，其机理尚不明确，限制Lst的实际应用。申请人前期研究发现，金葡菌对Lst的耐受性与细胞表面多糖复合物壁磷壁酸有关。据此，本项目将以壁磷壁酸的化学结构为切入点，建立小肠模拟环境，详细考察不同化学结构的壁磷壁酸对Lst的效用、以及对金葡菌Lst耐受性的影响，在分子层面阐明壁磷壁酸化学结构与金葡菌耐受性的关联机制。依此设计以壁磷壁酸为靶点、联合Lst的复合杀菌体系，在小肠模拟环境中高效专一地杀灭金葡菌。本项目有望为金葡菌在真实人体环境中耐受Lst的机理研究提供参考，为高效窄谱抗金葡菌疗法的开发提供新思路。

Staphylococcus aureus is a common pathogen, and the clinical treatment of S. aureus infections usually relies on antibiotics. However, antibiotics are wide-spectrum antimicrobial reagents, and their use always leads to many side effects including microbial imbalance in human bodies. A potential anti-S. aureus reagent with high activity and high specificity is lysostaphin (Lst). However, S. aureus is resistant to Lst in complicated environments such as blood and intestine. The underlying mechanism remains elusive, thus hindering the clinical application of Lst. It has been found in our earlier studies that S. aureus resistance to Lst is related to wall teichoic acid (WTA), the glycopolymer present on S. aureus cell surface. Based on this, we plan to study Lst resistance in S. aureus by focusing on WTA structure and by using a simulated small intestine environment. Through detailed investigations on the impact of WTA structure on Lst functionality and S. aureus tolerance of Lst, we will elucidate at the molecular level the relationship between WTA structure and S. aureus resistance to Lst and the underlying mechanism. According to such relationship, a complex anti-S. aureus system will be designed by targeting particular WTA structures and by combining the staphylolytic effect of Lst to achieve highly efficient, highly specific eradication of S. aureus in simulated small intestine environment. This study will shine light on the understanding of the mechanisms related to S. aureus resistance to Lst in actual human environments such as blood, intestine, etc., and will provide guidance to the development of potent and narrow-spectrum anti-S. aureus treatment.