Drug-resistant tuberculosis (TB) is a global threat and innovative approaches such as using adjuvants of anti-TB therapeutics are required to combat it. High-throughput screening yielded two lead scaffolds of inhibitors of Mycobacterium tuberculosis (Mtb) acetyltransferase Eis, whose upregulation causes resistance to the anti-TB drug kanamycin (KAN). Chemical optimization on these scaffolds resulted in potent Eis inhibitors. One compound restored the activity of KAN in a KAN-resistant Mtb strain. Model structures of Eis-inhibitor complexes explain the structure-activity relationship.
|Number of pages||3|
|Journal||ACS Medicinal Chemistry Letters|
|State||Published - Dec 8 2016|
Bibliographical noteFunding Information:
This work was supported by a NIH Grant AI090048 (S.G.-T.), a grant from theCCGat the U. Michigan (S.G.-T.), a grant from the Firland Foundation (S.G.-T.), and by startup funds from the College of Pharmacy at the U. Kentucky (S.G.-T. and O.V.T.).We thank Steve Vander Roest, Martha Larsen, and Paul Kirchhoff (CCG, UM) for help with HTS.
© 2016 American Chemical Society.
- Aminoglycoside acetyltransferase
- drug combination
- enzyme inactivation
- structure−activity relationship
ASJC Scopus subject areas
- Drug Discovery
- Organic Chemistry