Kinetic and Structural Characterization of the First B3 Metallo-β-Lactamase with an Active-Site Glutamic Acid

The structural diversity in metallo-β-lactamases (MBLs), especially in the vicinity of the active site, has been a major hurdle in the development of clinically effective inhibitors. Representatives from three variants of the B3 MBL subclass, containing either the canonical HHH/DHH active-site motif...

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Bibliographic Details
Published in:Antimicrobial agents and chemotherapy 2021-09, Vol.65 (10), p.e0093621
Main Authors: Wilson, Liam A, Knaven, Esmée G, Morris, Marc T, Monteiro Pedroso, Marcelo, Schofield, Christopher J, Brück, Thomas B, Boden, Mikael, Waite, David W, Hugenholtz, Philip, Guddat, Luke, Schenk, Gerhard
Format: Article
Language:English
Subjects:
Anti-Bacterial Agents - pharmacology
beta-Lactamase Inhibitors - pharmacology
beta-Lactamases - genetics
beta-Lactamases - metabolism
Catalytic Domain
Glutamic Acid
Mechanisms of Resistance
Molecular and Cellular Biology
Sphingomonadaceae - metabolism
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Summary:The structural diversity in metallo-β-lactamases (MBLs), especially in the vicinity of the active site, has been a major hurdle in the development of clinically effective inhibitors. Representatives from three variants of the B3 MBL subclass, containing either the canonical HHH/DHH active-site motif (present in the majority of MBLs in this subclass) or the QHH/DHH (B3-Q) or HRH/DQK (B3-RQK) variations, were reported previously. Here, we describe the structure and kinetic properties of the first example (SIE-1) of a fourth variant containing the EHH/DHH active-site motif (B3-E). SIE-1 was identified in the hexachlorocyclohexane-degrading bacterium Sphingobium indicum, and kinetic analyses demonstrate that although it is active against a wide range of antibiotics, its efficiency is lower than that of other B3 MBLs but has increased efficiency toward cephalosporins relative to other β-lactam substrates. The overall fold of SIE-1 is characteristic of the MBLs; the notable variation is observed in the Zn1 site due to the replacement of the canonical His116 by a glutamate. The unusual preference of SIE-1 for cephalosporins and its occurrence in a widespread environmental organism suggest the scope for increased MBL-mediated β-lactam resistance. Thus, it is relevant to include SIE-1 in MBL inhibitor design studies to widen the therapeutic scope of much needed antiresistance drugs.
ISSN:0066-4804
1098-6596
DOI:10.1128/AAC.00936-21