5Y5B
Crystal Structure Of IMP-1 Metallo-beta-lactamase
Summary for 5Y5B
| Entry DOI | 10.2210/pdb5y5b/pdb |
| Descriptor | Metallo-beta-lactamase type 2, ZINC ION, SULFATE ION, ... (5 entities in total) |
| Functional Keywords | hydrolase |
| Biological source | Serratia marcescens |
| Total number of polymer chains | 1 |
| Total formula weight | 25850.17 |
| Authors | Wachino, J. (deposition date: 2017-08-08, release date: 2018-08-08, Last modification date: 2023-11-22) |
| Primary citation | Wachino, J.,Kanechi, R.,Nishino, E.,Mochizuki, M.,Jin, W.,Kimura, K.,Kurosaki, H.,Arakawa, Y. 4-Amino-2-Sulfanylbenzoic Acid as a Potent Subclass B3 Metallo-beta-Lactamase-Specific Inhibitor Applicable for Distinguishing Metallo-beta-Lactamase Subclasses. Antimicrob.Agents Chemother., 63:-, 2019 Cited by PubMed Abstract: The number of cases of infection with carbapenem-resistant (CRE) has been increasing and has become a major clinical and public health concern. Production of metallo-β-lactamases (MBLs) is one of the principal carbapenem resistance mechanisms in CRE. Therefore, developing MBL inhibitors is a promising strategy to overcome the problems of carbapenem resistance conferred by MBLs. To date, the development and evaluation of MBL inhibitors have focused on subclass B1 MBLs but not on B3 MBLs. In the present study, we searched for B3 MBL (specifically, SMB-1) inhibitors and found thiosalicylic acid (TSA) to be a potent inhibitor of B3 SMB-1 MBL (50% inhibitory concentration [IC], 0.95 μM). TSA inhibited the purified SMB-1 to a considerable degree but was not active against cells producing SMB-1, as the meropenem (MEM) MIC for the SMB-1 producer was only slightly reduced with TSA. We then introduced a primary amine to TSA and synthesized 4-amino-2-sulfanylbenzoic acid (ASB), which substantially reduced the MEM MICs for SMB-1 producers. X-ray crystallographic analyses revealed that ASB binds to the two zinc ions, Ser221, and Thr223 at the active site of SMB-1. These are ubiquitously conserved residues across clinically relevant B3 MBLs. ASB also significantly inhibited other B3 MBLs, including AIM-1, LMB-1, and L1. Therefore, the characterization of ASB provides a starting point for the development of optimum B3 MBL inhibitors. PubMed: 31405855DOI: 10.1128/AAC.01197-19 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.7 Å) |
Structure validation
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