Identification through structure-based methods of a bacterial NAD(+)-dependent DNA ligase inhibitor that avoids known resistance mutations

Bioorg Med Chem Lett. 2014 Jan 1;24(1):360-6. doi: 10.1016/j.bmcl.2013.11.007. Epub 2013 Nov 15.

Abstract

In an attempt to identify novel inhibitors of NAD(+)-dependent DNA ligase (LigA) that are not affected by a known resistance mutation in the adenosine binding pocket, a detailed analysis of the binding sites of a variety of bacterial ligases was performed. This analysis revealed several similarities to the adenine binding region of kinases, which enabled a virtual screen of known kinase inhibitors. From this screen, a thienopyridine scaffold was identified that was shown to inhibit bacterial ligase. Further characterization through structure and enzymology revealed the compound was not affected by a previously disclosed resistance mutation in Streptococcus pneumoniae LigA, Leu75Phe. A subsequent medicinal chemistry program identified substitutions that resulted in an inhibitor with moderate activity across various Gram-positive bacterial LigA enzymes.

Keywords: Adenosine; Antibacterial; NAD(+)-dependent ligase; Resistance; Thienopyridine.

MeSH terms

  • DNA Ligases / antagonists & inhibitors*
  • DNA Ligases / metabolism
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Models, Molecular
  • Molecular Structure
  • Streptococcus pneumoniae / enzymology*
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • DNA Ligases
  • DNA ligase (NAD)