Bulgecin A, a sulphonated N-acetyl-D-glucosamine unit linked to a 4-hydroxy-5-hydroxymethylproline ring by a β-glycosidic linkage, is a novel type of inhibitor for binuclear metallo-β-lactamases. Using steady-state kinetic analysis with nitrocefin as the β-lactam substrate, bulgecin A competitively inhibited the metallo-β-lactamase BceII from Bacillus cereus in its two-zinc form, but failed to inhibit when the enzyme was in the single-zinc form. The competitive inhibition was restored by restoring the second zinc ion. The single-zinc metallo-β-lactamase from Aeromonas veronii bv. sobria, ImiS, was not inhibited by bulgecin A. The tetrameric L1 metallo-β-lactamase from Stenotrophomonas maltophilia was subject to partial non-competitive inhibition, which is consistent with a kinetic model in which the enzyme bound to inhibitor retains catalytic activity. Docking experiments support the conclusion that bulgecin A co-ordinates to the zinc II site in metallo-β-lactamases via the terminal sulphonate group on the sugar moiety.
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Research Article|
April 26 2005
Bulgecin A: a novel inhibitor of binuclear metallo-β-lactamases
Alan M. SIMM;
Alan M. SIMM
1
*Department of Pathology and Microbiology, University of Bristol, University Walk, Bristol BS8 1TD, U.K.
1To whom correspondence should be addressed (email A.M.Simm@bristol.ac.uk).
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E. Joel LOVERIDGE;
E. Joel LOVERIDGE
†Department of Chemistry, University of Bristol, Cantocks Close, Bristol BS8 1TS, U.K.
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John CROSBY;
John CROSBY
†Department of Chemistry, University of Bristol, Cantocks Close, Bristol BS8 1TS, U.K.
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Matthew B. AVISON;
Matthew B. AVISON
‡Department of Biochemistry, University of Bristol, University Walk, Bristol BS8 1TD, U.K.
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Timothy R. WALSH;
Timothy R. WALSH
*Department of Pathology and Microbiology, University of Bristol, University Walk, Bristol BS8 1TD, U.K.
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Peter M. BENNETT
Peter M. BENNETT
*Department of Pathology and Microbiology, University of Bristol, University Walk, Bristol BS8 1TD, U.K.
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Publisher: Portland Press Ltd
Received:
September 08 2004
Revision Received:
October 26 2004
Accepted:
November 30 2004
Accepted Manuscript online:
November 30 2004
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2005
Biochem J (2005) 387 (3): 585–590.
Article history
Received:
September 08 2004
Revision Received:
October 26 2004
Accepted:
November 30 2004
Accepted Manuscript online:
November 30 2004
Citation
Alan M. SIMM, E. Joel LOVERIDGE, John CROSBY, Matthew B. AVISON, Timothy R. WALSH, Peter M. BENNETT; Bulgecin A: a novel inhibitor of binuclear metallo-β-lactamases. Biochem J 1 May 2005; 387 (3): 585–590. doi: https://doi.org/10.1042/BJ20041542
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