High-throughput identification of antibacterials against methicillin-resistant Staphylococcus aureus (MRSA) and the transglycosylase

被引：61

作者：

Cheng, Ting-Jen Rachel ^{[1
]}

Wu, Ying-Ta ^{[1
]}

Yang, Shih-Ting ^{[1
]}

Lo, Kien-Hock ^{[1
]}

Chen, Shao-Kang ^{[1
]}

Chen, Yin-Hsuan ^{[1
]}

Huang, Wen-I ^{[1
]}

Yuan, Chih-Hung ^{[1
]}

Guo, Chih-Wei ^{[1
]}

Huang, Lin-Ya ^{[1
]}

Chen, Kuo-Ting ^{[1
]}

Shih, Hao-Wei ^{[1
]}

Cheng, Yih-Shyun E. ^{[1
]}

Cheng, Wei-Chieh ^{[1
]}

Wong, Chi-Huey ^{[1
]}

机构：

[1] Acad Sinica, Genom Res Ctr, Taipei 115, Taiwan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2010年 / 18卷 / 24期

关键词：

Transglycosylase; High-throughput screening; Methicillin-resistant Staphylococcus aureus (MRSA); Salicylanilide; CELL-WALL BIOSYNTHESIS; 1ST TOTAL-SYNTHESIS; ESCHERICHIA-COLI; ANTIBIOTIC-RESISTANCE; MOENOMYCIN-A; LIPID-II; INHIBITORS; BINDING; DOMAIN; SALICYLANILIDES;

D O I：

10.1016/j.bmc.2010.10.036

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

To identify new transglycosylase inhibitors with potent anti-methicillin-resistant Staphylococcus aureus (MRSA) activities, a high-throughput screening against Staphylococcus aureus was conducted to look for antibacterial cores in our 2 M compound library that consists of natural products, proprietary collection, and synthetic molecules. About 3600 hits were identified from the primary screening and the subsequent confirmation resulted in a total of 252 compounds in 84 clusters which showed anti-MRSA activities with MIC values as low as 0.1 mu g/ml. Subsequent screening targeting bacterial transglycosylase identified a salicylanilide-based core that inhibited the lipid II polymerization and the moenomycin-binding activities of transglycosylase. Among the collected analogues, potent inhibitors with the IC50 values below 10 mu M against transglycosylase were identified. The non-carbonhydrate scaffold reported in this study suggests a new direction for development of bacterial transglycosylase inhibitors. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：8512 / 8529

页数：18

共 37 条

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