9RJK

Structure of Mycobacterium tuberculosis InhA in complex with pyridomycin derivative KV41a (compound 11)

これはPDB形式変換不可エントリーです。

9RJK の概要

• エントリーDOI: 10.2210/pdb9rjk/pdb
• 関連するPDBエントリー: 9RJG 9RJH 9RJI 9RJJ 9RJL 9RJM 9RJN 9RJP
• 分子名称: Enoyl-[acyl-carrier-protein] reductase [NADH], ~{N}-[(2~{Z},5~{R},6~{S},9~{S},10~{S},11~{R})-2-butan-2-ylidene-5,11-dimethyl-10-oxidanyl-3,7,12-tris(oxidanylidene)-9-(pyridin-3-ylmethyl)-1,4-dioxa-8-azacyclododec-6-yl]-3-fluoranyl-2-oxidanyl-benzamide, DI(HYDROXYETHYL)ETHER, ... (4 entities in total)
• 機能のキーワード: inha mycobacterium tuberculosis pyridomycin derivative complex inhibitor, oxidoreductase
• 由来する生物種: Mycobacterium tuberculosis
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 117790.74

構造登録者

Publicola, G.,Mourey, L.,Valderrama, K.,Hartkoorn, R.,Maveyraud, L. (登録日: 2025-06-12, 公開日: 2026-02-11, 最終更新日: 2026-02-25)

主引用文献

Valderrama, K.,Horlacher, O.,Publicola, G.,Eisenring, P.,Kienle, M.,Boarbi, S.,Kiass, M.,Kordulakova, J.,Chatagnon, J.,Piveteau, C.,Leroux, F.,Savkova, K.,Zahorszka, M.,Cantrelle, F.X.,Lherbet, C.,Mourey, L.,Mikusova, K.,Mathys, V.,Aichholz, R.,Maveyraud, L.,Altmann, K.H.,Hartkoorn, R.C.
Optimizing the Antibiotic Potency and Metabolic Stability of Pyridomycin Using a Semisynthetic Approach.
J.Med.Chem., 69:2496-2508, 2026

PubMed Abstract: Pyridomycin is a natural product with potent activity against (), acting through direct inhibition of the fatty acid synthesis enzyme InhA. As a direct inhibitor, pyridomycin maintains activity on strains resistant to the InhA targeting prodrugs isoniazid and ethionamide. Evaluation of the drug-like properties of pyridomycin, however, found it to have poor metabolic stability, thus limiting its drug development potential. To address this limitation, semisynthetic derivatives were generated by replacing the metabolically labile hydroxypicolinic acid group with alternative (hetero)aromatic moieties, identifying several derivatives with improved metabolic stability and with comparable or even enhanced antibacterial activity. Pharmacokinetic studies in mice, however, revealed that these gains did not reduce systemic clearance , and neither pyridomycin nor its derivatives were effective in a murine pulmonary tuberculosis model. Overall, semisynthesis yielded more potent, P450-stable analogs, but the improvements were insufficient to provide measurable efficacy.

PubMed: 41591406
DOI: 10.1021/acs.jmedchem.5c02409

実験手法

X-RAY DIFFRACTION (1.658 Å)