Discovery and development of substituted thiadiazoles as inhibitors of Staphylococcus aureus Sortase A

被引：15

作者：

Wehrli, Patrick M. ^{[1
,2
]}

Uzelac, Ivana ^{[1
]}

Olsson, Thomas ^{[1
]}

Jacso, Tomas ^{[3
,4
]}

Tietze, Daniel ^{[1
]}

Gottfries, Johan ^{[1
,2
]}

机构：

[1] Univ Gothenburg, Dept Chem & Mol Biol, Gothenburg, Sweden

[2] Univ Gothenburg, Ctr Antibiot Resistance Res CARe, Gothenburg, Sweden

[3] AstraZeneca R&D, Struct & Biophys, Discovery Sci, Molndal, Sweden

[4] Nuevolution AB, Dept Biol, Early Discovery, Copenhagen, Denmark

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2019年 / 27卷 / 19期

关键词：

Staphylococcus aureus; Sortase A; SrtA inhibitors; Anti-virulence drugs; Antimicrobial resistance; SURFACE-PROTEINS; SIDE-CHAIN; RESISTANCE; VIRULENCE; ACCURACY; PHOSPHINES; MECHANISM; BACTERIA; DOCKING; TARGET;

D O I：

10.1016/j.bmc.2019.115043

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：

High-throughput screening of small-molecule libraries has led to the identification of thiadiazoles as a new class of inhibitors against Staphylococcus aureus sortase A (SrtA). N-(5-((4-nitrobenzyl) thio)-1,3,4-thiadiazol-2-yl)nicotinamide (IC50= 3.8 mu M) was identified as a potent inhibitor of SrtA after synthetic modification of hit compounds. Additional ligands developed in this study displayed affinities in the low micromolar range without affecting bacterial growth in vitro. The study also suggest a new mode of action through covalent binding to the active site cysteine.

引用

页数：11

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