ABSTRACT
The chromosome-encoded class C ß-lactamase CHE-1 produced by Enterobacter cloacae exhibits a lower sensitivity to avibactam than the P99 enzyme from which it is derived by a 6-residue deletion in the H-10 helix. In the present study, we investigated the sensitivity of CHE-1 to two other ß-lactamase inhibitors: LK-157 (or Lek 157), a tricyclic ß-lactam, and BAL29880, a bridged monobactam. With both compounds, the second-order rate constants for inactivation were significantly lower for CHE-1, which can thus be considered an inactivator-resistant mutant of P99. However, the second-order rate constant for the inactivation by BAL29880 probably remains adequate for a rather rapid reaction with CHE-1 in the absence of protection by the substrate.
Subject(s)
Azabicyclo Compounds/pharmacology , Carbapenems/pharmacology , Enterobacter cloacae/drug effects , Monobactams/pharmacology , Phenylurea Compounds/pharmacology , beta-Lactamase Inhibitors/pharmacology , beta-Lactamases/genetics , Enterobacter cloacae/enzymology , Enterobacter cloacae/genetics , beta-Lactamases/metabolismABSTRACT
Aminocitrate (and homolog) derivatives have been prepared by bis-alkylation of glycinate Schiff bases with bromoacetates (and ethyl acrylate), followed by N-acylation and esters (partial or complete) deprotection. Aminoisocitrate was similarly obtained by mono-alkylation with diethyl fumarate. Evaluation against representative beta-lactamases revealed that the free acid derivatives are modest inhibitors of class A enzymes, whilst their benzyl esters showed a good inhibition of OXA-10 (class D enzyme). A docking experiment featured hydrophobic interactions in the active site.