7UYA
Inhibitor bound VIM1
Summary for 7UYA
Entry DOI | 10.2210/pdb7uya/pdb |
Descriptor | Beta-lactamase VIM-1, ZINC ION, (2M)-4'-(piperidin-4-yl)-2-(1H-tetrazol-5-yl)[1,1'-biphenyl]-3-sulfonamide, ... (4 entities in total) |
Functional Keywords | hydrolase |
Biological source | Pseudomonas aeruginosa |
Total number of polymer chains | 1 |
Total formula weight | 26525.07 |
Authors | Fischmann, T.O.,Scapin, G. (deposition date: 2022-05-06, release date: 2023-05-24, Last modification date: 2024-03-27) |
Primary citation | Dong, S.,Zhao, Z.,Tang, H.,Li, G.,Pan, J.,Gu, X.,Jiang, J.,Xiao, L.,Scapin, G.,Hunter, D.N.,Yang, D.,Huang, Y.,Bennett, F.,Yang, S.W.,Mandal, M.,Tang, H.,Su, J.,Tudge, C.,deJesus, R.K.,Ding, F.X.,Lombardo, M.,Hicks, J.D.,Fischmann, T.,Mirza, A.,Dayananth, P.,Painter, R.E.,Villafania, A.,Garlisi, C.G.,Zhang, R.,Mayhood, T.W.,Si, Q.,Li, N.,Amin, R.P.,Bhatt, B.,Chen, F.,Regan, C.P.,Regan, H.,Lin, X.,Wu, J.,Leithead, A.,Pollack, S.R.,Scott, J.D.,Nargund, R.P.,Therien, A.G.,Black, T.,Young, K.,Pasternak, A. Structure Guided Discovery of Novel Pan Metallo-beta-Lactamase Inhibitors with Improved Gram-Negative Bacterial Cell Penetration. J.Med.Chem., 67:3400-3418, 2024 Cited by PubMed Abstract: The use of β-lactam (BL) and β-lactamase inhibitor combination to overcome BL antibiotic resistance has been validated through clinically approved drug products. However, unmet medical needs still exist for the treatment of infections caused by Gram-negative (GN) bacteria expressing metallo-β-lactamases. Previously, we reported our effort to discover pan inhibitors of three main families in this class: IMP, VIM, and NDM. Herein, we describe our work to improve the GN coverage spectrum in combination with imipenem and relebactam. This was achieved through structure- and property-based optimization to tackle the GN cell penetration and efflux challenges. A significant discovery was made that inhibition of both VIM alleles, VIM-1 and VIM-2, is essential for broad GN coverage, especially against VIM-producing . In addition, pharmacokinetics and nonclinical safety profiles were investigated for select compounds. Key findings from this drug discovery campaign laid the foundation for further lead optimization toward identification of preclinical candidates. PubMed: 38387069DOI: 10.1021/acs.jmedchem.3c01614 PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (1.01 Å) |
Structure validation
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