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.
Bibliographical noteFunding Information:
This study was funded by a National Institutes of Health (NIH) Grant AI090048 (S.G.-T.) a grant from the Firland Foundation (S.G.-T.), a grant from the Center for Chemical Genomics (CCG) at the University of Michigan (S.G.-T) and startup funds from the College of Pharmacy at the University of Kentucky (S.G.-T. and O.V.T.). S.Y.L.H. is partially supported by a University of Kentucky Presidential Fellowship.
- aminoglycoside acetyltransferase
- bacterial resistance
- drug combination
- enzyme inactivation
- structure-activity-relationship analysis