5K48

VIM-2 Metallo Beta Lactamase in complex with 3-(mercaptomethyl)-[1,1'-biphenyl]-4-carboxylic acid

Summary for 5K48

• Entry DOI: 10.2210/pdb5k48/pdb
• Descriptor: Beta-lactamase VIM-2, 4-phenyl-2-(sulfanylmethyl)benzoic acid, FORMIC ACID, ... (5 entities in total)
• Functional Keywords: metallo beta-lactamase, antibiotic resistance, carbapenamase. inhibitor, hydrolase
• Biological source: Pseudomonas aeruginosa
• Total number of polymer chains: 2
• Total formula weight: 52498.17

Authors

Zollman, D.,McDonough, M.,Brem, J.,Schofield, C. (deposition date: 2016-05-20, release date: 2017-06-07, Last modification date: 2024-01-10)

Primary citation

Cain, R.,Brem, J.,Zollman, D.,McDonough, M.A.,Johnson, R.M.,Spencer, J.,Makena, A.,Abboud, M.I.,Cahill, S.,Lee, S.Y.,McHugh, P.J.,Schofield, C.J.,Fishwick, C.W.G.
In Silico Fragment-Based Design Identifies Subfamily B1 Metallo-beta-lactamase Inhibitors.
J. Med. Chem., 61:1255-1260, 2018

PubMed Abstract: Zinc ion-dependent β-lactamases (MBLs) catalyze the hydrolysis of almost all β-lactam antibiotics and resist the action of clinically available β-lactamase inhibitors. We report how application of in silico fragment-based molecular design employing thiol-mediated metal anchorage leads to potent MBL inhibitors. The new inhibitors manifest potent inhibition of clinically important B1 subfamily MBLs, including the widespread NDM-1, IMP-1, and VIM-2 enzymes; with lower potency, some of them also inhibit clinically relevant Class A and D serine-β-lactamases. The inhibitors show selectivity for bacterial MBL enzymes compared to that for human MBL fold nucleases. Cocrystallization of one inhibitor, which shows potentiation of Meropenem activity against MBL-expressing Enterobacteriaceae, with VIM-2 reveals an unexpected binding mode, involving interactions with residues from conserved active site bordering loops.

PubMed: 29271657
DOI: 10.1021/acs.jmedchem.7b01728

Experimental method

X-RAY DIFFRACTION (1.744 Å)