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Discovery and Characterization of a Class of Pyrazole Inhibitors of Bacterial Undecaprenyl Pyrophosphate Synthase
dataset
posted on 2016-07-05, 00:00 authored by Nestor Concha, Jianzhong Huang, Xiaopeng Bai, Andrew Benowitz, Pat Brady, LaShadric
C. Grady, Luz Helena Kryn, David Holmes, Karen Ingraham, Qi Jin, Laura Pothier Kaushansky, Lynn McCloskey, Jeffrey A. Messer, Heather O’Keefe, Amish Patel, Alexander L. Satz, Robert H. Sinnamon, Jessica Schneck, Steve R. Skinner, Jennifer Summerfield, Amy Taylor, J. David Taylor, Ghotas Evindar, Robert A. StavengerUndecaprenyl
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.
