Combating Enhanced Intracellular Survival (Eis)-Mediated Kanamycin Resistance of Mycobacterium tuberculosis by Novel Pyrrolo[1,5-a]pyrazine-Based Eis Inhibitors

ACS Infect Dis. 2017 Apr 14;3(4):302-309. doi: 10.1021/acsinfecdis.6b00193. Epub 2017 Feb 17.


Tuberculosis (TB) remains one of the leading causes of mortality worldwide. Hence, the identification of highly effective antitubercular drugs with novel modes of action is crucial. In this paper, we report the discovery and development of pyrrolo[1,5-a]pyrazine-based analogues as highly potent inhibitors of the Mycobacterium tuberculosis (Mtb) acetyltransferase enhanced intracellular survival (Eis), whose up-regulation causes clinically observed resistance to the aminoglycoside (AG) antibiotic kanamycin A (KAN). We performed a structure-activity relationship (SAR) study to optimize these compounds as potent Eis inhibitors both against purified enzyme and in mycobacterial cells. A crystal structure of Eis in complex with one of the most potent inhibitors reveals that the compound is bound to Eis in the AG binding pocket, serving as the structural basis for the SAR. These Eis inhibitors have no observed cytotoxicity to mammalian cells and are promising leads for the development of innovative AG adjuvant therapies against drug-resistant TB.

Keywords: aminoglycoside acetyltransferase; bacterial resistance; drug combination; enzyme inactivation; structure−activity-relationship analysis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetyltransferases / antagonists & inhibitors
  • Acetyltransferases / chemistry
  • Antitubercular Agents / chemistry
  • Antitubercular Agents / pharmacology*
  • Bacterial Proteins / antagonists & inhibitors
  • Bacterial Proteins / chemistry
  • Binding Sites
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Gene Expression Regulation, Bacterial / drug effects
  • Gene Expression Regulation, Enzymologic / drug effects
  • Kanamycin Resistance / drug effects*
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / growth & development
  • Protein Binding
  • Pyrazines / chemistry
  • Pyrazines / pharmacology
  • Structure-Activity Relationship


  • Antitubercular Agents
  • Bacterial Proteins
  • Enzyme Inhibitors
  • Pyrazines
  • Acetyltransferases