6B3T

Crystal structure of acetyltransferase Eis from Mycobacterium tuberculosis in complex with a 1,2,4-triazino[5,6b]indole-3-thioether inhibitor analogue 39b

Summary for 6B3T

• Entry DOI: 10.2210/pdb6b3t/pdb
• Descriptor: N-acetyltransferase Eis, COENZYME A, 8-fluoro-5-methyl-3-{[2-(piperidin-1-yl)ethyl]sulfanyl}-5H-[1,2,4]triazino[5,6-b]indole, ... (6 entities in total)
• Functional Keywords: transferase, tuberculosis, aminoglycoside, resistance, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
• Total number of polymer chains: 1
• Total formula weight: 47231.14

Authors

Gajadeera, C.S.,Hou, C.,Garneau-Tsodikova, S.,Ngo, H.X.,Tsodikov, O.V. (deposition date: 2017-09-24, release date: 2018-04-04, Last modification date: 2023-10-04)

Primary citation

Ngo, H.X.,Green, K.D.,Gajadeera, C.S.,Willby, M.J.,Holbrook, S.Y.L.,Hou, C.,Garzan, A.,Mayhoub, A.S.,Posey, J.E.,Tsodikov, O.V.,Garneau-Tsodikova, S.
Potent 1,2,4-Triazino[5,6 b]indole-3-thioether Inhibitors of the Kanamycin Resistance Enzyme Eis from Mycobacterium tuberculosis.
ACS Infect Dis, 4:1030-1040, 2018

PubMed Abstract: 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.

PubMed: 29601176
DOI: 10.1021/acsinfecdis.8b00074

Experimental method

X-RAY DIFFRACTION (2.4 Å)