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Publication Abstract from PubMed

The structural diversity in metallo-beta-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 beta-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 beta-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.

Kinetic and Structural Characterization of the First B3 Metallo-beta-Lactamase with an Active-Site Glutamic Acid.,Wilson LA, Knaven EG, Morris MT, Monteiro Pedroso M, Schofield CJ, Bruck TB, Boden M, Waite DW, Hugenholtz P, Guddat L, Schenk G Antimicrob Agents Chemother. 2021 Sep 17;65(10):e0093621. doi:, 10.1128/AAC.00936-21. Epub 2021 Jul 26. PMID:34310207^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.