Abstract

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.

Links

Publisher Full Text

Authors

Yoshida T, Nasu H, Namba E, Ubukata O, Yamashita M

Institution

Biological Research Laboratories IV, Daiichi Sankyo Co. Ltd, 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan. yoshida.tatsuhiko.ej@daiichisankyo.co.jp

Source

Journal of medical microbiology 61:Pt 9 2012 Sep pg 1280-5

MeSH

Adenosine Triphosphatases
Anti-Bacterial Agents
Bacteria
Bacterial Proteins
Benzoic Acid
Carbon-Nitrogen Ligases
Cytidine Triphosphate
Enzyme Inhibitors
Haemophilus influenzae
Humans
Inhibitory Concentration 50
Microbial Sensitivity Tests
Respiratory Tract Infections
Staphylococcus aureus
Streptococcus pneumoniae
Uridine Triphosphate

Pub Type(s)

Journal Article

Language

eng

PubMed ID

22700553