3G1M

EthR from Mycobacterium tuberculosis in complex with compound BDM31381

3G1M の概要

• エントリーDOI: 10.2210/pdb3g1m/pdb
• 関連するPDBエントリー: 1U9N 1U9O 3G1L 3G1O
• 分子名称: TRANSCRIPTIONAL REGULATORY REPRESSOR PROTEIN (TETR-FAMILY) ETHR, 1-(thiophen-2-ylacetyl)-4-(3-thiophen-2-yl-1,2,4-oxadiazol-5-yl)piperidine (3 entities in total)
• 機能のキーワード: tetr family, dna-binding, transcription, transcription regulation
• 由来する生物種: Mycobacterium tuberculosis
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 26312.54

構造登録者

Willand, N.,Dirie, B.,Carette, X.,Bifani, P.,Singhal, A.,Desroses, M.,Leroux, F.,Willery, E.,Mathys, V.,Deprez-Poulain, R.,Delcroix, G.,Frenois, F.,Aumercier, M.,Locht, C.,Villeret, V.,Deprez, B.,Baulard, A.R. (登録日: 2009-01-30, 公開日: 2009-07-21, 最終更新日: 2024-02-21)

主引用文献

Willand, N.,Dirie, B.,Carette, X.,Bifani, P.,Singhal, A.,Desroses, M.,Leroux, F.,Willery, E.,Mathys, V.,Deprez-Poulain, R.,Delcroix, G.,Frenois, F.,Aumercier, M.,Locht, C.,Villeret, V.,Deprez, B.,Baulard, A.R.
Synthetic EthR inhibitors boost antituberculous activity of ethionamide.
Nat.Med. (N.Y.), 15:537-544, 2009

PubMed Abstract: The side effects associated with tuberculosis therapy bring with them the risk of noncompliance and subsequent drug resistance. Increasing the therapeutic index of antituberculosis drugs should thus improve treatment effectiveness. Several antituberculosis compounds require in situ metabolic activation to become inhibitory. Various thiocarbamide-containing drugs, including ethionamide, are activated by the mycobacterial monooxygenase EthA, the production of which is controlled by the transcriptional repressor EthR. Here we identify drug-like inhibitors of EthR that boost the bioactivation of ethionamide. Compounds designed and screened for their capacity to inhibit EthR-DNA interaction were co-crystallized with EthR. We exploited the three-dimensional structures of the complexes for the synthesis of improved analogs that boosted the ethionamide potency in culture more than tenfold. In Mycobacterium tuberculosis-infected mice, one of these analogs, BDM31343, enabled a substantially reduced dose of ethionamide to lessen the mycobacterial load as efficiently as the conventional higher-dose treatment. This provides proof of concept that inhibiting EthR improves the therapeutic index of thiocarbamide derivatives, which should prompt reconsideration of their use as first-line drugs.

PubMed: 19412174
DOI: 10.1038/nm.1950

実験手法

X-RAY DIFFRACTION (1.7 Å)