Wang Li, Li Qianxue, Li Jiaxin, Jing Shisong, Jin Yajing, Yang Lin, Yu Hangqian, Wang Dacheng, Wang Tiedong, Wang Lin
College of Animal Science, Jilin University, Changchun, China.
Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China.
Front Microbiol. 2021 Feb 18;12:635710. doi: 10.3389/fmicb.2021.635710. eCollection 2021.
New anti-infective approaches are urgently needed to control multidrug-resistant (MDR) pathogens, such as methicillin-resistant (MRSA). Sortase A (SrtA) is a membrane-bound cysteine transpeptidase that plays an essential role in the catalysis of covalent anchoring of surface proteins to the cell wall of (). The present study reports identification of a flavonoid, eriodictyol, as a reversible inhibitor of SrtA with an IC of 2.229 ± 0.014 μg/mL that can be used as an innovative means to counter both resistance and virulence. The data indicated that eriodictyol inhibited the adhesion of the bacteria to fibrinogen and reduced the formation of biofilms and anchoring of staphylococcal protein A (SpA) on the cell wall. The results of fluorescence quenching experiments demonstrated a strong interaction between eriodictyol and SrtA. Subsequent mechanistic studies revealed that eriodictyol binds to SrtA by interacting with R197 amino acid residue. Importantly, eriodictyol reduced the adhesion-dependent invasion of A549 cells by and showed a good therapeutic effect in a model of mouse pneumonia induced by . Overall, the results indicated that eriodictyol can attenuate MRSA virulence and prevent the development of resistance by inhibiting SrtA, suggesting that eriodictyol may be a promising lead compound for the control of MRSA infections.
迫切需要新的抗感染方法来控制耐多药（MDR）病原体，如耐甲氧西林金黄色葡萄球菌（MRSA）。分选酶A（SrtA）是一种膜结合的半胱氨酸转肽酶，在表面蛋白与（此处原文缺失相关内容）细胞壁的共价锚定催化中起关键作用。本研究报告了一种黄酮类化合物圣草酚被鉴定为SrtA的可逆抑制剂，其半数抑制浓度（IC）为2.229±0.014μg/mL，可作为对抗耐药性和毒力的创新手段。数据表明，圣草酚抑制细菌与纤维蛋白原的粘附，减少生物膜的形成以及葡萄球菌蛋白A（SpA）在细胞壁上的锚定。荧光猝灭实验结果表明圣草酚与SrtA之间存在强烈相互作用。随后的机制研究表明，圣草酚通过与R197氨基酸残基相互作用而与SrtA结合。重要的是，圣草酚使（此处原文缺失相关内容）对A549细胞的粘附依赖性侵袭减少，并在由（此处原文缺失相关内容）诱导的小鼠肺炎模型中显示出良好的治疗效果。总体而言，结果表明圣草酚可通过抑制SrtA来减弱MRSA的毒力并防止耐药性的产生，这表明圣草酚可能是控制MRSA感染的一种有前景的先导化合物。
