Discovery of a compound that acts as a bacterial PyrG (CTP synthase) inhibitor

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 mM, and the inhibitory activity of compound G1 was 13 times higher than that of acivicin (1.2 mM), 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.

CTP synthase: the hissing of the cellular serpent

“…Compound G1 could compete with ATP and/or UTP to bind with PyrG in order to inhibit CTPsyn activity. It was able to have anti-microbial property against different RTI causing bacteria (Yoshida et al 2012 ) Human immunodeficiency virus (HIV) Lamivudine (3TC), a deoxycytidine analogue, is used to treat HIV and its combination with 3-deazauridine or acivicin (both are CTPsyn inhibitors) increases anti-HIV activity significantly and halts HIV replication (Dereuddre-Bosquet et al 2004 )

Fig. 8 Mechanism of SARS-CoV-2 exploiting CTPS1 for immune evasion, survival, and replication.

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Functional Annotation of Hypothetical Proteins From the Enterobacter cloacae B13 Strain and Its Association With Pathogenicity

“…93,94 TOZ46383.1 was found to be a CTP synthase, which converts UTP to CTP, a necessary step in pyrimidine metabolic pathway in community-acquired respiratory tract infection (RTI) causing bacteria. 95 In addition, TOZ48266.1 was identified as an ABC transporter 6-transmembrane domain-containing protein, which are considered to have roles in nutrient uptake and drug resistance. Moreover, evidence of ABC transporters being directly or indirectly involved in the bacterial virulence has been found.…”

A metal‐dependent conformational change provides a structural basis for the inhibition of CTP synthase by gemcitabine‐5′‐triphosphate

“…Due to its essential role in maintaining the intracellular CTP pool, CTPS has been long recognized as a therapeutic target for developing drugs directed at protozoan parasites (Fijolek et al, 2007 ; Hofer et al, 2001 ; Lim et al, 1996 ), bacterial (Mori et al, 2015 ; Yoshida et al, 2012 ) and viral infections (Andrei & de Clercq, 1993 ; de Clercq, 1993 ; de Clercq et al, 1991 ; Kang et al, 1989 ), and cancers (McPartland et al, 1974 ; Toschi et al, 2005 ). One notable compound, gemcitabine‐5′‐triphosphate (2′,2′‐difluoro‐5′‐deoxycytidine‐5′‐triphosphate, dF‐dCTP, Table 1 ) has long been utilized as a therapeutic agent against solid tumors (Heinemann et al, 1995 ; Toschi et al, 2005 ).…”