8R5T
Crystal structure of NDM-1 in complex with benzobisheterocycle compound 14.
Summary for 8R5T
| Entry DOI | 10.2210/pdb8r5t/pdb |
| Descriptor | Metallo-beta-lactamase type 2, [(1~{R},3~{a}~{R})-1,3,3~{a},4-tetrahydro-[1,3]thiazolo[3,4-a]benzimidazol-1-yl]methanethiol, ZINC ION, ... (5 entities in total) |
| Functional Keywords | metallo-beta-lactamase, inhibitor, antimicrobial protein |
| Biological source | Klebsiella pneumoniae |
| Total number of polymer chains | 2 |
| Total formula weight | 52230.01 |
| Authors | |
| Primary citation | Villamil, V.,Rossi, M.A.,Mojica, M.F.,Hinchliffe, P.,Martinez, V.,Castillo, V.,Saiz, C.,Banchio, C.,Macias, M.A.,Spencer, J.,Bonomo, R.A.,Vila, A.,Moreno, D.M.,Mahler, G. Rational Design of Benzobisheterocycle Metallo-beta-Lactamase Inhibitors: A Tricyclic Scaffold Enhances Potency against Target Enzymes. J.Med.Chem., 67:3795-3812, 2024 Cited by PubMed Abstract: Antimicrobial resistance is a global public health threat. Metallo-β-lactamases (MBLs) inactivate β-lactam antibiotics, including carbapenems, are disseminating among Gram-negative bacteria, and lack clinically useful inhibitors. The evolving bisthiazolidine (BTZ) scaffold inhibits all three MBL subclasses (B1-B3). We report design, synthesis, and evaluation of BTZ analogues. Structure-activity relationships identified the BTZ thiol as essential, while carboxylate is replaceable, with its removal enhancing potency by facilitating hydrophobic interactions within the MBL active site. While the introduction of a flexible aromatic ring is neutral or detrimental for inhibition, a rigid (fused) ring generated nM benzobisheterocycle (BBH) inhibitors that potentiated carbapenems against MBL-producing strains. Crystallography of BBH:MBL complexes identified hydrophobic interactions as the basis of potency toward B1 MBLs. These data underscore BTZs as versatile, potent broad-spectrum MBL inhibitors (with activity extending to enzymes refractory to other inhibitors) and provide a rational approach to further improve the tricyclic BBH scaffold. PubMed: 38373290DOI: 10.1021/acs.jmedchem.3c02209 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.58 Å) |
Structure validation
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