4P8O

S. aureus gyrase bound to an aminobenzimidazole urea inhibitor

Summary for 4P8O

• Entry DOI: 10.2210/pdb4p8o/pdb
• Descriptor: DNA gyrase subunit B, 1-ethyl-3-[5-(5-fluoropyridin-3-yl)-7-(pyrimidin-2-yl)-1H-benzimidazol-2-yl]urea (3 entities in total)
• Functional Keywords: antibacterial, gram-positive, gyrase, topoisomerase, staphylococcus aureus, isomerase
• Biological source: Staphylococcus aureus
• Cellular location: Cytoplasm : Q6GKU0
• Total number of polymer chains: 2
• Total formula weight: 43644.65

Authors

Jacobs, M.D. (deposition date: 2014-03-31, release date: 2014-10-29, Last modification date: 2023-12-27)

Primary citation

Grillot, A.L.,Tiran, A.L.,Shannon, D.,Krueger, E.,Liao, Y.,O'Dowd, H.,Tang, Q.,Ronkin, S.,Wang, T.,Waal, N.,Li, P.,Lauffer, D.,Sizensky, E.,Tanoury, J.,Perola, E.,Grossman, T.H.,Doyle, T.,Hanzelka, B.,Jones, S.,Dixit, V.,Ewing, N.,Liao, S.,Boucher, B.,Jacobs, M.,Bennani, Y.,Charifson, P.S.
Second-generation antibacterial benzimidazole ureas: discovery of a preclinical candidate with reduced metabolic liability.
J.Med.Chem., 57:8792-8816, 2014

PubMed Abstract: Compound 3 is a potent aminobenzimidazole urea with broad-spectrum Gram-positive antibacterial activity resulting from dual inhibition of bacterial gyrase (GyrB) and topoisomerase IV (ParE), and it demonstrates efficacy in rodent models of bacterial infection. Preclinical in vitro and in vivo studies showed that compound 3 covalently labels liver proteins, presumably via formation of a reactive metabolite, and hence presented a potential safety liability. The urea moiety in compound 3 was identified as being potentially responsible for reactive metabolite formation, but its replacement resulted in loss of antibacterial activity and/or oral exposure due to poor physicochemical parameters. To identify second-generation aminobenzimidazole ureas devoid of reactive metabolite formation potential, we implemented a metabolic shift strategy, which focused on shifting metabolism away from the urea moiety by introducing metabolic soft spots elsewhere in the molecule. Aminobenzimidazole urea 34, identified through this strategy, exhibits similar antibacterial activity as that of 3 and did not label liver proteins in vivo, indicating reduced/no potential for reactive metabolite formation.

PubMed: 25317480
DOI: 10.1021/jm500563g

Experimental method

X-RAY DIFFRACTION (2.4 Å)