7P2M
E.coli GyrB24 with inhibitor LMD43 (EBL2560)
Summary for 7P2M
| Entry DOI | 10.2210/pdb7p2m/pdb |
| Descriptor | 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) |
| Functional Keywords | gyrase, inhibitor, e.coli, complex, dna binding protein |
| Biological source | Escherichia coli (strain K12) |
| Total number of polymer chains | 1 |
| Total formula weight | 24762.49 |
| Authors | 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. (deposition date: 2021-07-06, release date: 2022-07-20, Last modification date: 2024-01-31) |
| Primary citation | 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 Cited by 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: 36634346DOI: 10.1021/acs.jmedchem.2c01597 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.16 Å) |
Structure validation
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