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

doi:10.1039/d1md00316j

	Covalent sortase A inhibitor ML346 prevents Staphylococcus aureus infection of Galleria mellonella
	Guan, Xiang-Na 1,2; Zhang, Tao 1; Yang, Teng 1,3; Dong, Ze 1; Yang, Song 3; Lan, Lefu 1,2,4; Gan, Jianhua 5; Yang, Cai-Guang 1,2,4
刊名	RSC MEDICINAL CHEMISTRY
	2021-11-01
页码	12
DOI	10.1039/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.
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关键词	SURFACE-PROTEINS ; CELL-WALL ; IN-VITRO ; VIRULENCE ; TRANSPEPTIDASE ; TARGET ; SRTA ; ENZYME ; MODEL
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
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/298680]
专题	中国科学院上海药物研究所
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.