Reversible inhibitors of penicillinases

Abstract

Reversible competitive inhibitors of a penicillinase, .beta.-lactamase I from Bacillus cereus, were studied. These represent the 1st inhibitors of a penicillinase that lack the .beta.-lactam ring. The products of the enzymic reaction, namely penicilloic acids, are inhibitors; their decarboxylation products, the penilloic acids, are also inhibitors, and have somewhat lower Ki values. Inhibitors were prepared from benzylpenicillin, phenoxymethylpenicillin, methicillin (2,6-dimethoxybenzamidopenicillanic acid) and 3-hydroxy-4-nitrobenzamidopenicillanic acid. Decarboxylation of the penicilloic acids from benzylpenicillin, or from phenoxymethylpenicillin, leads to epimerization (at C-5) of the penilloic acid. NMR spectroscopy at a frequency of 270 MHz can distinguish the epimers. Other competitive inhibitors studied were boric acid, benzene-boronic acid and m-aminobenzeneboronic acid. Boric acid itself was the best inhibitor of .beta.-lactamase I so far found.