9C1C

Mycobacterium tuberculosis PKS13 acyltransferase serine converted to beta-lactam form by CEC215 via SuFEx reaction

これはPDB形式変換不可エントリーです。

9C1C の概要

• エントリーDOI: 10.2210/pdb9c1c/pdb
• 関連するPDBエントリー: 9C1D
• 分子名称: Polyketide synthase Pks13, SULFATE ION, CHLORIDE ION, ... (10 entities in total)
• 機能のキーワード: inhibitor, sufex, acyltransferase, structural genomics, tb structural genomics consortium, tbsgc, antibiotic
• 由来する生物種: Mycobacterium tuberculosis H37Rv; 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 162959.68

構造登録者

Tang, S.,Sacchettini, J.C.,TB Structural Genomics Consortium (TBSGC) (登録日: 2024-05-29, 公開日: 2025-05-21, 最終更新日: 2025-10-01)

主引用文献

Krieger, I.V.,Sukheja, P.,Yang, B.,Tang, S.,Selle, D.,Woods, A.,Engelhart, C.,Kumar, P.,Harbut, M.B.,Liu, D.,Tsuda, B.,Qin, B.,Bare, G.A.L.,Li, G.,Chi, V.,Gambacurta, J.,Hvizdos, J.,Reagan, M.,Jones, I.L.,Massoudi, L.M.,Woolhiser, L.K.,Cascioferro, A.,Kundrick, E.,Singh, P.,Reiley, W.,Ioerger, T.R.,Kandula, D.R.,McCabe, J.W.,Guo, T.,Alland, D.,Boshoff, H.I.,Schnappinger, D.,Robertson, G.T.,Mdluli, K.,Lee, K.J.,Dong, J.,Li, S.,Schultz, P.G.,Joseph, S.B.,Love, M.S.,Sharpless, K.B.,Petrassi, H.M.,Chatterjee, A.K.,Sacchettini, J.C.,McNamara, C.W.
SuFEx-based antitubercular compound irreversibly inhibits Pks13.
Nature, 645:755-763, 2025

PubMed Abstract: Mycobacterium tuberculosis (Mtb) remains the world's deadliest bacterial pathogen. There is an urgent medical need to develop new drugs that shorten the treatment duration to combat widespread multi-drug-resistant and extensive-drug-resistant Mtb. Here, we present a preclinical covalent compound, CMX410, that contains an aryl fluorosulfate (SuFEx) warhead and uniquely targets the acyltransferase domain of Pks13, an essential enzyme in cell-wall biosynthesis. CMX410 is equipotent against drug-sensitive and drug-resistant strains of Mtb and efficacious in multiple mouse models of infection. Inhibition by CMX410 is irreversible through a previously undescribed mechanism: CMX410 reacts with the catalytic serine of the AT domain of Pks13, rapidly and irreversibly disabling the active site by forming a β-lactam. CMX410 is highly selective for its target and thus demonstrates excellent pharmacological and safety profiles, including no adverse effects in a 14-day rat toxicity study up to 1,000 mg kg per day. The distinctive mode of action from current drugs, high potency across all tested clinical isolates, oral bioavailability, favourable performance in drug combination testing and superior pharmacological and safety characteristics make CMX410 a promising first-in-class candidate to replace outdated cell-wall biosynthesis inhibitors, such as isoniazid and ethambutol, in tuberculosis regimens.

PubMed: 40739353
DOI: 10.1038/s41586-025-09286-3

実験手法

X-RAY DIFFRACTION (2.22 Å)