Open AccessPotent 1,2,4-Triazino[5,6b]indole-3-thioether Inhibitors of the Kanamycin Resistance Enzyme Eis from Mycobacterium tuberculosis
Author(s) -
Huy Ngo,
Keith D. Green,
Chathurada S. Gajadeera,
Melisa J. Willby,
Selina Y. L. Holbrook,
Can Hou,
Atefeh Garzan,
Abdelrahman S. Mayhoub,
James E. Posey,
Oleg V. Tsodikov,
Sylvie GarneauTsodikova
Publication year - 2018
Publication title -
acs infectious diseases
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.324
H-Index - 39
ISSN - 2373-8227
DOI - 10.1021/acsinfecdis.8b00074
Subject(s) - mycobacterium tuberculosis , chemistry , indole test , kanamycin , enzyme , thioether , microbiology and biotechnology , pharmacology , stereochemistry , biochemistry , biology , tuberculosis , medicine , antibiotics , pathology
A common cause of resistance to kanamycin (KAN) in tuberculosis is overexpression of the enhanced intracellular survival (Eis) protein. Eis is an acetyltransferase that multiacetylates KAN and other aminoglycosides, rendering them unable to bind the bacterial ribosome. By high-throughput screening, a series of substituted 1,2,4-triazino[5,6 b]indole-3-thioether molecules were identified as effective Eis inhibitors. Herein, we purchased 17 and synthesized 22 new compounds, evaluated their potency, and characterized their steady-state kinetics. Four inhibitors were found not only to inhibit Eis in vitro, but also to act as adjuvants of KAN and partially restore KAN sensitivity in a Mycobacterium tuberculosis KAN-resistant strain in which Eis is upregulated. A crystal structure of Eis in complex with a potent inhibitor and CoA shows that the inhibitors bind in the aminoglycoside binding site snugly inserted into a hydrophobic cavity. These inhibitors will undergo preclinical development as novel KAN adjuvant therapies to treat KAN-resistant tuberculosis.