title: Discovery of inhibitors of Bacillus anthracis primase DnaG.
abstract: 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 nonradioactive 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-micromolar Ba DnaG inhibitor, was recently shown to be also a low-micromolar inhibitor of Mycobacterium tuberculosis DnaG (Mtb DnaG). In contrast, another low-micromolar 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.
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Tapan
authors.initials: T
authors.lastname: Biswas
authors.forename: Keith D
authors.initials: KD
authors.lastname: Green
authors.forename: Sylvie
authors.initials: S
authors.lastname: Garneau-Tsodikova
authors.forename: Oleg V
authors.initials: OV
authors.lastname: Tsodikov
mesh_terms: D000818:Animals; D001408:Bacillus anthracis / Q000201:enzymology*; D002478:Cells, Cultured; D019915:DNA Primase / Q000037:antagonists & inhibitors* / Q000302:isolation & purification / Q000378:metabolism; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D057166:High-Throughput Screening Assays; D064704:Levofloxacin / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013498:Suramin / Q000737:chemistry / Q000494:pharmacology; D013994:Tilorone / Q000737:chemistry / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D013498:Suramin; D064704:Levofloxacin; D004317:Doxorubicin; D019915:DNA Primase; D013994:Tilorone