Boronic acid-based b-lactamase inhibitors were first reported in 1978 , and these were gradually improved to mimic the structures of the natural b-lactamase substrates . A patent involving boronic acid inhibitors designed to structurally mimic the penicillin side chain was filed in 2007 .The chemical complexity of boronic acids has gradually increased, as shown in Figure 1 .
Figure 1. Chemical structure of recent boronic acids.
Initial studies showed that sulfonamide boronic acid inhibitors can reduce the MIC of ceftazidime by 4- to 16-fold against b-lactamase producing Gram-negative strains, including P. aeruginosa . Further refinement using a fragment-based approach led to the tetrazole shown, which can lower MICs in AmpC-overproducing E. coli by as much as 256-fold and shows efficacy in a murine model . Last, a library of triazole-substituted boronic acids was generated using a ‘click chemistry’ approach and selected boronic acids were shown to have ability to inhibit class A and class C b-lactamases, including the KPC-2 carbapenemase, and to display synergy with ampicillin against several strains of b-lactamase producing E. coli .
The cyclic boronates (i.e., 1,5,2-dioxaborepane-2-ols) were shown to lower the MIC of tigemonam against class A ESBLs as well as C- and D-producing strains of E. coli and K. pneumoniae .
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