6b3t
Crystal structure of acetyltransferase Eis from Mycobacterium tuberculosis in complex with a 1,2,4-triazino[5,6b]indole-3-thioether inhibitor analogue 39bCrystal structure of acetyltransferase Eis from Mycobacterium tuberculosis in complex with a 1,2,4-triazino[5,6b]indole-3-thioether inhibitor analogue 39b
Structural highlights
FunctionEIS_MYCTU May participate in pathogenesis, possibly by enhancing survival of the bacteria in host macrophages during infection.[1] Publication Abstract from PubMedA 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. Potent 1,2,4-Triazino[5,6 b]indole-3-thioether Inhibitors of the Kanamycin Resistance Enzyme Eis from Mycobacterium tuberculosis.,Ngo HX, Green KD, Gajadeera CS, Willby MJ, Holbrook SYL, Hou C, Garzan A, Mayhoub AS, Posey JE, Tsodikov OV, Garneau-Tsodikova S ACS Infect Dis. 2018 Mar 30. doi: 10.1021/acsinfecdis.8b00074. PMID:29601176[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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