Aminopyrazinamides: novel and specific GyrB inhibitors that kill replicating and nonreplicating Mycobacterium tuberculosis

ACS Chem Biol. 2013 Mar 15;8(3):519-23. doi: 10.1021/cb300510w. Epub 2012 Dec 31.


Aminopyrazinamides originated from a high throughput screen targeting the Mycobacterium smegmatis (Msm) GyrB ATPase. This series displays chemical tractability, robust structure-activity relationship, and potent antitubercular activity. The crystal structure of Msm GyrB in complex with one of the aminopyrazinamides revealed promising attributes of specificity against other broad spectrum pathogens and selectivity against eukaryotic kinases due to novel interactions at hydrophobic pocket, unlike other known GyrB inhibitors. The aminopyrazinamides display excellent mycobacterial kill under in vitro, intracellular, and hypoxic conditions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA Gyrase / metabolism*
  • Dose-Response Relationship, Drug
  • Models, Molecular
  • Molecular Structure
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / enzymology
  • Mycobacterium tuberculosis / growth & development*
  • Pyrazines / chemistry
  • Pyrazines / pharmacology*
  • Structure-Activity Relationship
  • Topoisomerase II Inhibitors / chemistry
  • Topoisomerase II Inhibitors / pharmacology*


  • Pyrazines
  • Topoisomerase II Inhibitors
  • DNA Gyrase