Discovery of inhibitors of Bacillus anthracis primase DnaG.

Biochemistry

PubMedID: 24004110

Biswas T, Green KD, Garneau-Tsodikova S, Tsodikov OV. Discovery of inhibitors of Bacillus anthracis primase DnaG. Biochemistry. 2013;.
Primase DnaG is an essential bacterial enzyme that synthesizes short ribonucleotide primers required for chromosomal DNA replication. Inhibitors of DnaG can serve as leads for development of new antibacterials and biochemical probes. We recently developed a non-radioactive in vitro primase-pyrophosphatase assay to identify and analyze DnaG inhibitors. Application of this assay to DnaG from Bacillus anthracis (Ba DnaG), a dangerous pathogen, yielded several inhibitors, which include agents with DNA intercalating properties (doxorubicin and tilorone) as well as those that do not intercalate into DNA (suramin). A polyanionic agent and inhibitor of eukaryotic primases, suramin, identified by this assay as a low-µM Ba DnaG inhibitor, was recently shown to be also a low-µM inhibitor of Mycobacterium tuberculosis DnaG (Mtb DnaG). In contrast, another low-µM Ba DnaG inhibitor, tilorone, is much more potent against Ba DnaG than against Mtb DnaG, despite homology between these enzymes, suggesting that DnaG can be targeted selectively.