Bulgecin A: a novel inhibitor of binuclear metallo-β-lactamases

• Published in: Biochemical journal Vol. 387; no. 3; pp. 585 - 590
• Main Authors: SIMM, Alan M., LOVERIDGE, E. Joel, CROSBY, John, AVISON, Matthew B., WALSH, Timothy R., BENNETT, Peter M.
• Format: Journal Article
• Language: English
• Published: England Portland Press Ltd 01.05.2005
• Subjects: Acetylglucosamine - analogs & derivatives; Acetylglucosamine - chemistry; Acetylglucosamine - pharmacology; Aeromonas - enzymology; Aeromonas veronii; Bacillus cereus; Bacillus cereus - enzymology; Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - chemistry; Bacterial Proteins - metabolism; beta-Lactamase Inhibitors; beta-Lactamases - chemistry; beta-Lactamases - metabolism; Binding Sites; Dose-Response Relationship, Drug; Enzyme Inhibitors - pharmacology; Kinetics; Molecular Structure; Proline - analogs & derivatives; Proline - chemistry; Proline - pharmacology; Stenotrophomonas maltophilia; Stenotrophomonas maltophilia - enzymology; Zinc - chemistry
• ISSN: 0264-6021; 1470-8728; 1470-8728
• DOI: 10.1042/BJ20041542

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.