AUTHOR=Emami Kaveh , Wu Ling Juan , Errington Jeff 

TITLE=A Small Molecule Inhibitor of CTP Synthetase Identified by Differential Activity on a Bacillus subtilis Mutant Deficient in Class A Penicillin-Binding Proteins

JOURNAL=Frontiers in Microbiology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2020.02001

DOI=10.3389/fmicb.2020.02001

ISSN=1664-302X

ABSTRACT=<p>In the course of screening for compounds with differential growth inhibition activity on a mutant of <italic>Bacillus subtilis</italic> lacking all four class A penicillin-binding proteins (<italic>Δ4</italic>), we came across an isoquinoline derivative, IQ-1 carboxylic acid (IQC) with relatively high activity on the mutant compared to the wild type strain. Treated cells were slightly elongated and had altered chromosome morphology. Mutants of <italic>Δ4</italic> resistant to IQC were isolated and subjected to whole genome sequencing. Most of the mutants were affected in the gene, <italic>pyrG</italic>, encoding CTP synthetase (CTPS). Purified wild type CTPS was inhibited <italic>in vitro</italic> by IQC. Two of the three mutant proteins purified showed decreased sensitivity to IQC <italic>in vitro</italic>. Finally, inhibition by IQC was rescued by addition of cytidine but not uridine to the growth medium, consistent with the notion that IQC acts by reducing the synthesis of CTP or a related compound. IQC provides a promising new starting point for antibiotic inhibitors of CTPS.</p>