Competitive inhibitors of the CphA metallo-beta-lactamase from Aeromonas hydrophila.
Various inhibitors of metallo-beta-lactamases have been reported; however, none are effective for all subgroups. Those that have been found to inhibit the enzymes of subclass B2 (catalytically active with one zinc) either contain a thiol (and show less inhibition towards this subgroup than towards the dizinc members of B1 and B3) or are inactivators behaving as substrates for the dizinc family members. The present work reveals that certain pyridine carboxylates are competitive inhibitors of CphA, a subclass B2 enzyme. X-ray crystallographic analyses demonstrate that pyridine-2,4-dicarboxylic acid chelates the zinc ion in a bidentate manner within the active site. Salts of these compounds are already available and undergoing biomedical testing for various nonrelated purposes. Pyridine carboxylates appear to be useful templates for the development of more-complex, selective, nontoxic inhibitors of subclass B2 metallo-beta-lactamases.
Horsfall
L E
LE
Centre d'Ingéniérie des Protéines, Université de Liège, Allée de 6 Aout B6, Sart-Tilman, Liège, Belgium.
Garau
G
G
Liénard
B M R
BM
Dideberg
O
O
Schofield
C J
CJ
Frère
J M
JM
Galleni
M
M
D016980:Aeromonas hydrophila / Q000187:drug effects* / Q000201:enzymology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D001667:Binding, Competitive; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010848:Picolinic Acids / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000737:chemistry
D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D010848:Picolinic Acids; D011725:Pyridines; D065093:beta-Lactamase Inhibitors; C055293:2,4-pyridinedicarboxylic acid; D001618:beta-Lactamases; C082063:cphA protein, Aeromonas hydrophila; C030614:picolinic acid