Discovery of a compound that acts as a bacterial PyrG (CTP synthase) inhibitor.
PyrG (CTP synthase) catalyses the conversion of UTP to CTP, an essential step in the pyrimidine metabolic pathway in a variety of bacteria, including those causing community-acquired respiratory tract infections (RTIs). In this study, a luminescence-based ATPase assay of PyrG was developed and used to evaluate the inhibitory activity of 2-(3-[3-oxo-1,2-benzisothiazol-2(3H)-yl]phenylsulfonylamino) benzoic acid (compound G1). Compound G1 inhibited PyrG derived from Streptococcus pneumoniae with a 50 % inhibitory concentration value of 0.091 µM, and the inhibitory activity of compound G1 was 13 times higher than that of acivicin (1.2 µM), an established PyrG inhibitor. The results of saturation transfer difference analysis using nuclear magnetic resonance spectroscopy suggested that these compounds compete with ATP and/or UTP for binding to Strep. pneumoniae PyrG. Finally, compound G1 was shown to have antimicrobial activity against several different bacteria causing RTIs, such as Staphylococcus aureus and Haemophilus influenzae, suggesting that it is a prototype chemical compound that could be harnessed as an antimicrobial drug with a novel structure to target bacterial PyrG.
Biological Research Laboratories IV, Daiichi Sankyo Co. Ltd, 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan.
Tatsuhiko
T
Yoshida
Biological Research Laboratories IV, Daiichi Sankyo Co. Ltd, 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan.
Hatsumi
H
Nasu
Biological Research Laboratories IV, Daiichi Sankyo Co. Ltd, 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan.
Eiko
E
Namba
Core Technology Research Laboratories, Daiichi Sankyo Co. Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
Osamu
O
Ubukata
Biological Research Laboratories IV, Daiichi Sankyo Co. Ltd, 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan.
Makoto
M
Yamashita
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects* / Q000201:enzymology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors; D019817:Benzoic Acid / Q000737:chemistry / Q000494:pharmacology; D019731:Carbon-Nitrogen Ligases / Q000037:antagonists & inhibitors*; D003570:Cytidine Triphosphate / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006193:Haemophilus influenzae / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests / Q000379:methods; D012141:Respiratory Tract Infections / Q000382:microbiology*; D013211:Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology; D013296:Streptococcus pneumoniae / Q000187:drug effects / Q000201:enzymology; D014544:Uridine Triphosphate / Q000378:metabolism
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D003570:Cytidine Triphosphate; D019817:Benzoic Acid; D000251:Adenosine Triphosphatases; D019731:Carbon-Nitrogen Ligases; C019951:CTP synthetase; D014544:Uridine Triphosphate