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

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: 38387069
DOI: 10.1021/acs.jmedchem.3c01614

Experimental method

X-RAY DIFFRACTION (1.01 Å)