Discovery and Characterization of a Class of Pyrazole Inhibitors of Bacterial Undecaprenyl Pyrophosphate Synthase
Discovery and Characterization of a Class of Pyrazole Inhibitors of Bacterial Undecaprenyl Pyrophosphate Synthase
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DOI：
10.1021/acs.jmedchem.6b00746
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发表时间：
2016-08-11
影响因子：
7.3
通讯作者：
Stavenger, Robert A.
中科院分区：
文献类型：
--
作者：
Concha, Nestor;Huang, Jianzhong;Stavenger, Robert A.
十一烯酰焦磷酸合成酶（UppS）是细菌细胞壁合成的必需酶。在这里，我们报告了从编码文库技术筛选中发现的金黄色葡萄球菌UppS抑制剂，并通过共晶学研究证明其与疏水底物位点结合。通过调节uppS表达的菌株和抑制剂耐药突变体的研究，证实了全细胞活性是uppS抑制的结果，验证了uppS是一个可药物化的抗菌靶点。
Undecaprenyl pyrophosphate synthase (UppS) is an essential enzyme in bacterial cell wall synthesis. Here we report the discovery of Staphylococcus aureus UppS inhibitors from an Encoded Library Technology screen and demonstrate binding to the hydrophobic substrate site through cocrystallography studies. The use of bacterial strains with regulated uppS expression and inhibitor resistant mutant studies confirmed that the whole cell activity was the result of UppS inhibition, validating UppS as a druggable antibacterial target.