6YD9

Ecoli GyrB24 with inhibitor 16a

Summary for 6YD9

• Entry DOI: 10.2210/pdb6yd9/pdb
• Descriptor: DNA gyrase subunit B, N-[6-(3-azanylpropanoylamino)-1,3-benzothiazol-2-yl]-3,4-bis(chloranyl)-5-methyl-1H-pyrrole-2-carboxamide, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: dna gyrase, topoisomerase iv, inhibitor, dna binding protein
• Biological source: Escherichia coli (strain K12)
• Total number of polymer chains: 1
• Total formula weight: 24727.61

Authors

Barancokova, M.,Skok, Z.,Benek, O.,Cruz, C.D.,Tammela, P.,Tomasic, T.,Zidar, N.,Masic, L.P.,Zega, A.,Stevenson, C.E.M.,Mundy, J.,Lawson, D.M.,Maxwell, A.M.,Kikelj, D.,Ilas, J. (deposition date: 2020-03-20, release date: 2020-12-30, Last modification date: 2024-01-24)

Primary citation

Skok, Z.,Barancokova, M.,Benek, O.,Cruz, C.D.,Tammela, P.,Tomasic, T.,Zidar, N.,Masic, L.P.,Zega, A.,Stevenson, C.E.M.,Mundy, J.E.A.,Lawson, D.M.,Maxwell, A.,Kikelj, D.,Ilas, J.
Exploring the Chemical Space of Benzothiazole-Based DNA Gyrase B Inhibitors.
Acs Med.Chem.Lett., 11:2433-2440, 2020

PubMed Abstract: We designed and synthesized a series of inhibitors of the bacterial enzymes DNA gyrase and DNA topoisomerase IV, based on our recently published benzothiazole-based inhibitor bearing an oxalyl moiety. To improve the antibacterial activity and retain potent enzymatic activity, we systematically explored the chemical space. Several strategies of modification were followed: varying substituents on the pyrrole carboxamide moiety, alteration of the central scaffold, including variation of substitution position and, most importantly, modification of the oxalyl moiety. Compounds with acidic, basic, and neutral properties were synthesized. To understand the mechanism of action and binding mode, we have obtained a crystal structure of compound , bearing a primary amino group, in complex with the N-terminal domain of gyrase B (24 kDa) (PDB: ). Compound , with a low molecular weight of 383 Da, potent inhibitory activity on gyrase (IC = 9.5 nM), potent antibacterial activity on (MIC = 3.13 μM), and efflux impaired strain (MIC = 0.78 μM), is an important contribution for the development of novel gyrase and topoisomerase IV inhibitors in Gram-negative bacteria.

PubMed: 33329764
DOI: 10.1021/acsmedchemlett.0c00416

Experimental method

X-RAY DIFFRACTION (1.6 Å)