Discovery and Characterization of a Class of Pyrazole Inhibitors of Bacterial Undecaprenyl Pyrophosphate Synthase

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.

脱帽甾基焦磷酸合成酶（UppS）是细菌细胞壁合成过程中的关键酶。本研究报道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，并通过共晶学研究表明其与疏水性底物结合位点存在相互作用。利用调控uppS表达的细菌菌株以及抑制剂耐药突变体研究证实，全细胞活性系UppS抑制的结果，从而验证了UppS作为可药物化抗菌靶点的价值。