5IV0

Crystal structure of Eis from Mycobacterium tuberculosis in complex with sulfonamide inhibitor 39 and coenzyme A

5IV0 の概要

• エントリーDOI: 10.2210/pdb5iv0/pdb
• 分子名称: Enhanced intracellular survival protein, COENZYME A, N-(3-methoxyphenyl)-N-methyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-sulfonamide, ... (5 entities in total)
• 機能のキーワード: transferase, acetyltransferase, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Mycobacterium tuberculosis (strain CDC 1551 / Oshkosh)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 47896.10

構造登録者

Gajadeera, C.S.,Hou, C.,Garneau-Tsodikova, S.,Tsodikov, O.V. (登録日: 2016-03-18, 公開日: 2017-01-11, 最終更新日: 2024-03-06)

主引用文献

Garzan, A.,Willby, M.J.,Green, K.D.,Gajadeera, C.S.,Hou, C.,Tsodikov, O.V.,Posey, J.E.,Garneau-Tsodikova, S.
Sulfonamide-Based Inhibitors of Aminoglycoside Acetyltransferase Eis Abolish Resistance to Kanamycin in Mycobacterium tuberculosis.
J. Med. Chem., 59:10619-10628, 2016

PubMed Abstract: A two-drug combination therapy where one drug targets an offending cell and the other targets a resistance mechanism to the first drug is a time-tested, yet underexploited approach to combat or prevent drug resistance. By high-throughput screening, we identified a sulfonamide scaffold that served as a pharmacophore to generate inhibitors of Mycobacterium tuberculosis acetyltransferase Eis, whose upregulation causes resistance to the aminoglycoside (AG) antibiotic kanamycin A (KAN) in Mycobacterium tuberculosis. Rational systematic derivatization of this scaffold to maximize Eis inhibition and abolish the Eis-mediated KAN resistance of M. tuberculosis yielded several highly potent agents. A crystal structure of Eis in complex with one of the most potent inhibitors revealed that the inhibitor bound Eis in the AG-binding pocket held by a conformationally malleable region of Eis (residues 28-37) bearing key hydrophobic residues. These Eis inhibitors are promising leads for preclinical development of innovative AG combination therapies against resistant TB.

PubMed: 27933949
DOI: 10.1021/acs.jmedchem.6b01161

実験手法

X-RAY DIFFRACTION (2.1 Å)