Bulgecin A: a novel inhibitor of binuclear metallo-beta-lactamases.
Bulgecin A, a sulphonated N-acetyl-D-glucosamine unit linked to a 4-hydroxy-5-hydroxymethylproline ring by a beta-glycosidic linkage, is a novel type of inhibitor for binuclear metallo-beta-lactamases. Using steady-state kinetic analysis with nitrocefin as the beta-lactam substrate, bulgecin A competitively inhibited the metallo-beta-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-beta-lactamase from Aeromonas veronii bv. sobria, ImiS, was not inhibited by bulgecin A. The tetrameric L1 metallo-beta-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-beta-lactamases via the terminal sulphonate group on the sugar moiety.
Simm
Alan M
AM
Department of Pathology and Microbiology, University of Bristol, University Walk, Bristol BS8 1TD, UK. A.M.Simm@bristol.ac.uk
Loveridge
E Joel
EJ
Crosby
John
J
Avison
Matthew B
MB
Walsh
Timothy R
TR
Bennett
Peter M
PM
D000117:Acetylglucosamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000333:Aeromonas / Q000201:enzymology; D001409:Bacillus cereus / Q000201:enzymology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007700:Kinetics; D015394:Molecular Structure; D011392:Proline / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D020615:Stenotrophomonas maltophilia / Q000201:enzymology; D015032:Zinc / Q000737:chemistry; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000737:chemistry / Q000378:metabolism
D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D065093:beta-Lactamase Inhibitors; C405349:bulgecin A; D011392:Proline; C111082:ImiS protein, Aeromonas veronii; D001618:beta-Lactamases; C496277:metallo-beta-lactamase L1, Stenotrophomonas maltophilia; D015032:Zinc; D000117:Acetylglucosamine