6SP6
Ultra-high Resolution Crystal Structure of the CTX-M-15 Extended-Spectrum beta-Lactamase in Complex with Taniborbactam (VNRX-5133)
Summary for 6SP6
| Entry DOI | 10.2210/pdb6sp6/pdb |
| Descriptor | Beta-lactamase, SULFATE ION, (3~{R})-3-[2-[4-(2-azanylethylamino)cyclohexyl]ethanoylamino]-2-oxidanyl-3,4-dihydro-1,2-benzoxaborinine-8-carboxylic acid, ... (6 entities in total) |
| Functional Keywords | beta-lactamase, hydrolase, antibiotic resistance, beta-lactam hydrolysis |
| Biological source | Escherichia coli |
| Total number of polymer chains | 1 |
| Total formula weight | 29154.57 |
| Authors | Docquier, J.D.,Pozzi, C.,De Luca, F.,Benvenuti, M.,Mangani, S. (deposition date: 2019-08-31, release date: 2020-01-22, Last modification date: 2024-10-16) |
| Primary citation | Liu, B.,Trout, R.E.L.,Chu, G.H.,McGarry, D.,Jackson, R.W.,Hamrick, J.C.,Daigle, D.M.,Cusick, S.M.,Pozzi, C.,De Luca, F.,Benvenuti, M.,Mangani, S.,Docquier, J.D.,Weiss, W.J.,Pevear, D.C.,Xerri, L.,Burns, C.J. Discovery of Taniborbactam (VNRX-5133): A Broad-Spectrum Serine- and Metallo-beta-lactamase Inhibitor for Carbapenem-Resistant Bacterial Infections. J.Med.Chem., 63:2789-2801, 2020 Cited by PubMed Abstract: A major resistance mechanism in Gram-negative bacteria is the production of β-lactamase enzymes. Originally recognized for their ability to hydrolyze penicillins, emergent β-lactamases can now confer resistance to other β-lactam drugs, including both cephalosporins and carbapenems. The emergence and global spread of β-lactamase-producing multi-drug-resistant "superbugs" has caused increased alarm within the medical community due to the high mortality rate associated with these difficult-to-treat bacterial infections. To address this unmet medical need, we initiated an iterative program combining medicinal chemistry, structural biology, biochemical testing, and microbiological profiling to identify broad-spectrum inhibitors of both serine- and metallo-β-lactamase enzymes. Lead optimization, beginning with narrower-spectrum, weakly active compounds, provided (VNRX-5133, taniborbactam), a boronic-acid-containing pan-spectrum β-lactamase inhibitor. In vitro and in vivo studies demonstrated that restored the activity of β-lactam antibiotics against carbapenem-resistant and carbapenem-resistant Enterobacteriaceae. Taniborbactam is the first pan-spectrum β-lactamase inhibitor to enter clinical development. PubMed: 31765155DOI: 10.1021/acs.jmedchem.9b01518 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.1 Å) |
Structure validation
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