Reference : Thiomandelic acid, a broad spectrum inhibitor of zinc beta-lactamases: kinetic and sp...
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
Thiomandelic acid, a broad spectrum inhibitor of zinc beta-lactamases: kinetic and spectroscopic studies.
Mollard, C. [> > > >]
Moali, C. [> > > >]
Papamicael, C. [> > > >]
Damblon, Christian mailto [Université de Liège - ULg > Département de chimie (sciences) > Chimie biologique structurale >]
Vessilier, S. [> > > >]
Amicosante, G. [> > > >]
Schofield, C. J. [> > > >]
Galleni, Moreno mailto [Université de Liège - ULg > Département des sciences de la vie > Macromolécules biologiques >]
Frère, Jean-Marie mailto [Université de Liège - ULg > > Centre d'ingénierie des protéines >]
Roberts, G. C. [> > > >]
Journal of Biological Chemistry
American Society for Biochemistry and Molecular Biology
Yes (verified by ORBi)
[en] Arginine/chemistry ; Binding Sites ; Enzyme Inhibitors/pharmacology ; Kinetics ; Magnetic Resonance Spectroscopy ; Mandelic Acids/chemical synthesis/chemistry/metabolism ; Models, Chemical ; Models, Molecular ; Protein Binding ; Spectrophotometry ; Structure-Activity Relationship ; Sulfhydryl Compounds/chemical synthesis/chemistry/metabolism ; Zinc/chemistry/metabolism ; beta-Lactamases/antagonists & inhibitors
[en] Resistance to beta-lactam antibiotics mediated by metallo-beta-lactamases is an increasingly worrying clinical problem. Candidate inhibitors include mercaptocarboxylic acids, and we report studies of a simple such compound, thiomandelic acid. A series of 35 analogues were synthesized and examined as metallo-beta-lactamase inhibitors. The K(i) values (Bacillus cereus enzyme) are 0.09 microm for R-thiomandelic acid and 1.28 microm for the S-isomer. Structure-activity relationships show that the thiol is essential for activity and the carboxylate increases potency; the affinity is greatest when these groups are close together. Thioesters of thiomandelic acid are substrates for the enzyme, liberating thiomandelic acid, suggesting a starting point for the design of "pro-drugs." Importantly, thiomandelic acid is a broad spectrum inhibitor of metallo-beta-lactamases, with a submicromolar K(i) value for all nine enzymes tested, except the Aeromonas hydrophila enzyme; such a wide spectrum of activity is unprecedented. The binding of thiomandelic acid to the B. cereus enzyme was studied by NMR; the results are consistent with the idea that the inhibitor thiol binds to both zinc ions, while its carboxylate binds to Arg(91). Amide chemical shift perturbations for residues 30-40 (the beta(3)-beta(4) loop) suggest that this small inhibitor induces a movement of this loop of the kind seen for other larger inhibitors.

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