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Covalent sortase A inhibitor ML346 prevents Staphylococcus aureus infection of Galleria mellonella

文献类型：期刊论文

作者Guan, Xiang-Na1,2; Zhang, Tao1; Yang, Teng1,3; Dong, Ze1; Yang, Song3; Lan, Lefu1,2,4; Gan, Jianhua5; Yang, Cai-Guang1,2,4
刊名RSC MEDICINAL CHEMISTRY
出版日期2021-11-01
页码12
DOI10.1039/d1md00316j
通讯作者Yang, Cai-Guang(yangcg@simm.ac.cn)
英文摘要The housekeeping sortase A (SrtA), a membrane-associated cysteine transpeptidase, is responsible for anchoring surface proteins to the cell wall peptidoglycan in Gram-positive bacteria. This process is essential for the regulation of bacterial virulence and pathogenicity. Therefore, SrtA is considered to be an ideal target for antivirulence therapy. In this study, we report that ML346, a compound with a barbituric acid and cinnamaldehyde scaffold, functions as an irreversible inhibitor of Staphylococcus aureus SrtA (SaSrtA) and Streptococcus pyogenes SrtA (SpSrtA) in vitro at low micromolar concentrations. According to our X-ray crystal structure of the SpSrtA(Delta N81)/ML346 complex (Protein Data Bank ID: 7V6K), ML346 covalently modifies the thiol group of Cys208 in the active site of SpSrtA. Importantly, ML346 significantly attenuated the virulence phenotypes of S. aureus and exhibited inhibitory effects on Galleria mellonella larva infection caused by S. aureus. Collectively, our results indicate that ML346 has potential for development as a covalent antivirulence agent for treating S. aureus infections, including methicillin-resistant S. aureus.
WOS关键词SURFACE-PROTEINS ; CELL-WALL ; IN-VITRO ; VIRULENCE ; TRANSPEPTIDASE ; TARGET ; SRTA ; ENZYME ; MODEL
资助项目National Natural Science Foundation of China[22107109] ; National Natural Science Foundation of China[81861138046] ; National Natural Science Foundation of China[21725801]
WOS研究方向Biochemistry & Molecular Biology ; Pharmacology & Pharmacy
语种英语
出版者ROYAL SOC CHEMISTRY
WOS记录号WOS:000717120300001
源URL[http://119.78.100.183/handle/2S10ELR8/298680]  
专题新药研究国家重点实验室
通讯作者Yang, Cai-Guang
作者单位1.Chinese Acad Sci, Ctr Chem Biol, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
3.Guizhou Univ, Ctr R&D Fine Chem, State Key Lab Breeding Base Green Pesticide & Agr, Key Lab Green Pesticide & Agr Bioengn,Minist Educ, Guiyang 550025, Peoples R China
4.Univ Chinese Acad Sci, Sch Pharmaceut Sci & Technol, Hangzhou Inst Adv Study, Hangzhou 310024, Peoples R China
5.Fudan Univ, Sch Life Sci, Shanghai 200433, Peoples R China
推荐引用方式
GB/T 7714		 Guan, Xiang-Na,Zhang, Tao,Yang, Teng,et al. Covalent sortase A inhibitor ML346 prevents Staphylococcus aureus infection of Galleria mellonella[J]. RSC MEDICINAL CHEMISTRY,2021:12.
APA Guan, Xiang-Na.,Zhang, Tao.,Yang, Teng.,Dong, Ze.,Yang, Song.,...&Yang, Cai-Guang.(2021).Covalent sortase A inhibitor ML346 prevents Staphylococcus aureus infection of Galleria mellonella.RSC MEDICINAL CHEMISTRY,12.
MLA Guan, Xiang-Na,et al."Covalent sortase A inhibitor ML346 prevents Staphylococcus aureus infection of Galleria mellonella".RSC MEDICINAL CHEMISTRY (2021):12.

入库方式： OAI收割

来源：上海药物研究所

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