Title: A close look onto structural models and primary ligands of metallo-β-lactamases

Abstract

β-Lactamases are hydrolytic enzymes capable of opening the β-lactam ring of antibiotics such as penicillin, thus endowing the bacteria that produce them with antibiotic resistance. Of particular medical concern are metallo-β-lactamases (MBLs), with an active site built around coordinated Zn cations. MBLs are pan-reactive enzymes that can break down almost all classes of β-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 β-lactamase databases. Here, we conducted a careful review of the crystal structures of class B β-lactamases, concluding that the quality of these structures varies widely, especially in the regions where small molecules interactmore » 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 In four cases, these models, prepared jointly with the authors of the original depositions, superseded the previous deposits.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.« less

Authors:

Raczynska, Joanna E. ^[1]; Shabalin, Ivan G. ^[2]; Minor, Wladek ^[2]; Wlodawer, Alexander ^[3]; Jaskolski, Mariusz ^[4]

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+ Show Author Affiliations

1. Polish Academy of Sciences (PAS), Poznan (Poland)
2. Univ. of Virginia, Charlottesville, VA (United States); Center for Structural Genomics of Infectious Diseases, Charlottesville, VA (United States)
3. National Cancer Institute, Frederick, MD (United States)
4. Polish Academy of Sciences (PAS), Poznan (Poland); Adam Mickiewicz Univ., Poznan (Poland)

Publication Date:

Sat Aug 25 00:00:00 EDT 2018

Research Org.:

Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Org.:

USDOE; National Institutes of Health (NIH)

OSTI Identifier:

1570745

Grant/Contract Number:  

GM117325; HG008424; HHSN272201200026C; HHSN272201700060C

Resource Type:

Accepted Manuscript

Journal Name:

Drug Resistance Updates

Additional Journal Information:

Journal Volume: 40; Journal Issue: 09; Journal ID: ISSN 1368-7646

Publisher:

Elsevier

Country of Publication:

United States

Language:

ENGLISH

Subject:

60 APPLIED LIFE SCIENCES; antibiotic resistance; metallo-β-lactamase; New Delhi metallo-β-lactamase (NDM); drug design target; metal coordination; structural databases; data mining; Protein Data Bank (PDB); reproducibility; model validation; structure re-deposition