Biochem. J. (2005) 387
(585–590) (Printed in Great Britain)
Bulgecin A: a novel inhibitor of binuclear metallo-b-lactamases
Alan M. SIMM*1, E. Joel LOVERIDGE†, John CROSBY†, Matthew B. AVISON‡, Timothy R. WALSH* and Peter M. BENNETT*
*Department of Pathology and Microbiology, University of Bristol, University Walk, Bristol BS8 1TD, U.K., †Department of Chemistry, University of Bristol, Cantocks Close, Bristol BS8 1TS, U.K., and ‡Department of Biochemistry, University of Bristol, University Walk, Bristol BS8 1TD, U.K.
Bulgecin A, a sulphonated N-acetyl-D-glucosamine unit linked to a 4-hydroxy-5-hydroxymethylproline ring by a b-glycosidic linkage, is a novel type of inhibitor for binuclear metallo-b-lactamases. Using steady-state kinetic analysis with nitrocefin as the b-lactam substrate, bulgecin A competitively inhibited the metallo-b-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-b-lactamase from Aeromonas veronii bv. sobria, ImiS, was not inhibited by bulgecin A. The tetrameric L1 metallo-b-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-b-lactamases via the terminal sulphonate group on the sugar moiety.
Key words: antibiotic resistance, bulgecin A, inhibitor, metallo-b-lactamase, Stenotrophomonas, zinc co-ordination.
Abbreviations used: AAS, atomic absorption spectroscopy; SLT70, 70-kDa soluble lytic transglycosylase.
1To whom correspondence should be addressed (email A.M.Simm@bristol.ac.uk).
Received 8 September 2004/26 October 2004; accepted 30 November 2004
Published as BJ Immediate Publication 30 November 2004, DOI 10.1042/BJ20041542
The Biochemical Society, London ©2005
Editorial Advisory Panel
RSS feeds
Table of contents by email
My BJ toolbox
