7P2M

E.coli GyrB24 with inhibitor LMD43 (EBL2560)

7P2M の概要

• エントリーDOI: 10.2210/pdb7p2m/pdb
• 分子名称: DNA gyrase subunit B, PHOSPHATE ION, 2-[[3,4-bis(chloranyl)-5-methyl-1~{H}-pyrrol-2-yl]carbonylamino]-4-phenylmethoxy-1,3-benzothiazole-6-carboxylic acid, ... (4 entities in total)
• 機能のキーワード: gyrase, inhibitor, e.coli, complex, dna binding protein
• 由来する生物種: Escherichia coli (strain K12)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 24762.49

構造登録者

Stevenson, C.E.M.,Lawson, D.M.,Maxwell, A.M.,Henderson, S.R.,Kikelj, D.,Durcik, M.,Zega, A.,Zidar, N.,Ilas, J.,Tomasic, T.,Masic, L.P. (登録日: 2021-07-06, 公開日: 2022-07-20, 最終更新日: 2024-01-31)

主引用文献

Cotman, A.E.,Durcik, M.,Benedetto Tiz, D.,Fulgheri, F.,Secci, D.,Sterle, M.,Mozina, S.,Skok, Z.,Zidar, N.,Zega, A.,Ilas, J.,Peterlin Masic, L.,Tomasic, T.,Hughes, D.,Huseby, D.L.,Cao, S.,Garoff, L.,Berruga Fernandez, T.,Giachou, P.,Crone, L.,Simoff, I.,Svensson, R.,Birnir, B.,Korol, S.V.,Jin, Z.,Vicente, F.,Ramos, M.C.,de la Cruz, M.,Glinghammar, B.,Lenhammar, L.,Henderson, S.R.,Mundy, J.E.A.,Maxwell, A.,Stevenson, C.E.M.,Lawson, D.M.,Janssen, G.V.,Sterk, G.J.,Kikelj, D.
Discovery and Hit-to-Lead Optimization of Benzothiazole Scaffold-Based DNA Gyrase Inhibitors with Potent Activity against Acinetobacter baumannii and Pseudomonas aeruginosa.
J.Med.Chem., 66:1380-1425, 2023

PubMed Abstract: We have developed compounds with a promising activity against and , which are both on the WHO priority list of antibiotic-resistant bacteria. Starting from DNA gyrase inhibitor , we identified compound , featuring a 10-fold improved aqueous solubility, a 10-fold improved inhibition of topoisomerase IV from and , a 10-fold decreased inhibition of human topoisomerase IIα, and no cross-resistance to novobiocin. Cocrystal structures of in complex with GyrB24 and ()- in complex with GyrB23 and GyrB24 revealed their binding to the ATP-binding pocket of the GyrB subunit. In further optimization steps, solubility, plasma free fraction, and other ADME properties of were improved by fine-tuning of lipophilicity. In particular, analogs of with retained anti-Gram-negative activity and improved plasma free fraction were identified. The series was found to be nongenotoxic, nonmutagenic, devoid of mitochondrial toxicity, and possessed no ion channel liabilities.

PubMed: 36634346
DOI: 10.1021/acs.jmedchem.2c01597

実験手法

X-RAY DIFFRACTION (1.16 Å)