Structure-based inhibitors exhibit differential activities against Helicobacter pylori and Escherichia coli undecaprenyl pyrophosphate synthases.
Helicobacter pylori colonizes the human gastric epithelium and causes diseases such as gastritis, peptic ulcers, and stomach cancer. Undecaprenyl pyrophosphate synthase (UPPS), which catalyzes consecutive condensation reactions of farnesyl pyrophosphate with eight isopentenyl pyrophosphate to form lipid carrier for bacterial peptidoglycan biosynthesis, represents a potential target for developing new antibiotics. In this study, we solved the crystal structure of H. pylori UPPS and performed virtual screening of inhibitors from a library of 58,635 compounds. Two hits were found to exhibit differential activities against Helicobacter pylori and Escherichia coli UPPS, giving the possibility of developing antibiotics specially targeting pathogenic H. pylori without killing the intestinal E. coli.
Kuo
Chih-Jung
CJ
Taiwan International Graduate Program, Academia Sinica, Taipei 115, Taiwan.
Guo
Rey-Ting
RT
Lu
I-Lin
IL
Liu
Hun-Ge
HG
Wu
Su-Ying
SY
Ko
Tzu-Ping
TP
Wang
Andrew H-J
AH
Liang
Po-Huang
PH
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000648:ultrastructure*; D001665:Binding Sites; D003198:Computer Simulation; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000737:chemistry*; D004795:Enzyme Stability; D004926:Escherichia coli / Q000201:enzymology*; D016480:Helicobacter pylori / Q000201:enzymology*; D008956:Models, Chemical; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation
D004791:Enzyme Inhibitors; D019883:Alkyl and Aryl Transferases; C023266:undecaprenyl pyrophosphate synthetase