Structural highlights
Function
[BLAN1_KLEPN] Confers resistance to many beta-lactam antibiotics, including some carbapenems. Does not confer resistance to the polymixin colistin or the fluoroquinolone ciprofloxacin.
Publication Abstract from PubMed
beta-Lactamases are hydrolytic enzymes capable of opening the beta-lactam ring of antibiotics such as penicillin, thus endowing the bacteria that produce them with antibiotic resistance. Of particular medical concern are metallo-beta-lactamases (MBLs), with an active site built around coordinated Zn cations. MBLs are pan-reactive enzymes that can break down almost all classes of beta-lactams, including such last-resort antibiotics as carbapenems. They are not only broad-spectrum-reactive but are often plasmid-borne (e.g., the New Delhi enzyme, NDM), and can spread horizontally even among unrelated bacteria. Acquired MBLs are encoded by mobile genetic elements, which often include other resistance genes, making the microbiological situation particularly alarming. There is an urgent need to develop MBL inhibitors in order to rescue our antibiotic armory. A number of such efforts have been undertaken, most notably using the 3D structures of various MBLs as drug-design targets. Structure-guided drug discovery depends on the quality of the structures that are collected in the Protein Data Bank (PDB) and on the consistency of the information in dedicated beta-lactamase databases. We conducted a careful review of the crystal structures of class B beta-lactamases, concluding that the quality of these structures varies widely, especially in the regions where small molecules interact with the macromolecules. In a number of examples the interpretation of the bound ligands (e.g., inhibitors, substrate/product analogs) is doubtful or even incorrect, and it appears that in some cases the modeling of ligands was not supported by electron density. For ten MBL structures, alternative interpretations of the original diffraction data could be proposed and the new models have been deposited in the PDB. In four cases, these models, prepared jointly with the authors of the original depositions, superseded the previous deposits. This review emphasizes the importance of critical assessment of structural models describing key drug design targets at the level of the raw experimental data. Since the structures reviewed here are the basis for ongoing design of new MBL inhibitors, it is important to identify and correct the problems with ambiguous crystallographic interpretations, thus enhancing reproducibility in this highly medically relevant area.
A close look onto structural models and primary ligands of metallo-beta-lactamases.,Raczynska JE, Shabalin IG, Minor W, Wlodawer A, Jaskolski M Drug Resist Updat. 2018 Sep;40:1-12. doi: 10.1016/j.drup.2018.08.001. Epub 2018, Aug 25. PMID:30466711[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Raczynska JE, Shabalin IG, Minor W, Wlodawer A, Jaskolski M. A close look onto structural models and primary ligands of metallo-beta-lactamases. Drug Resist Updat. 2018 Sep;40:1-12. doi: 10.1016/j.drup.2018.08.001. Epub 2018, Aug 25. PMID:30466711 doi:https://dx.doi.org/10.1016/j.drup.2018.08.001
