Salicyloyl Cyclic Phosphate, a “Penicillin-Like” Inhibitor of β-Lactamases

Abstract

Salicyloyl cyclic phosphate (1-hydroxy-4,5-benzo-2,6-dioxaphosphorinanone (3)-1-oxide) was designed as a “penicillin-like” inhibitor of β-lactamases. It was anticipated that, after nucleophilic attack on this molecule by the enzyme, the leaving group would remain tethered, and, as in the inhibition of DD-peptidases by penicillins, obstruct hydrolysis of the covalent intermediate back to free enzyme. The target molecule, hitherto only reported as a transient intermediate, was prepared by hydrolysis of the cognate cyclic phosphoryl chloride and isolated and characterized as the dicyclohexylammonium salt. It proved to transiently inhibit the class C β-lactamase of Enterobacter cloacae P99, the class A TEM β-lactamase, and also the DD-peptidase of Streptomyces R61. Most significantly, the half-lives of the complexes formed with these enzymes were 14, 140, and 340 min, respectively. Thus, this cyclic phosphate represents a new class of molecule leading to inert complexes of β-lactam-recognizing enzymes.