Selectivity of inhibition of N-succinyl-L,L-diaminopimelic acid desuccinylase in bacteria : the product of dape-gene is not the target of L-captopril antimicrobial activity

Abstract

The emergence of bacterial strains that are resistant to virtually all currently available antibiotics underscores the importance of developing new antimicrobial compounds. N-succinyl-L,L-diaminopimelic acid desuccinylase (DapE) is a metallohydrolase involved in the meso-diaminopimelate (mDAP)/lysine biosynthetic pathway necessary for lysine biosynthesis and for building the peptidoglycan cell wall. Because DapE is essential for Gram-negative and some Gram-positive bacteria, DapE has been proposed as a good target for antibiotic development. Recently, L-captopril has been suggested as a lead compound for inhibition of DapE, although its selectivity for this enzyme target in bacteria remains unclear (Gillner et al. (2009)). Here, we tested the selectivity of L-captopril againstDapE in bacteria. SinceDapE knockout strains of gram-negative bacteria are viable upon chemicalsupplementation with mDAP, we reasoned that the antimicrobial activity of compounds targeting DapE should be abolished in mDAP-containing media. Although L-captopril had modest antimicrobial activity in Escherichia coli and in Salmonella enterica, to our surprise, inhibition of bacterial growth was independent both of mDAP supplementation and DapE over-expression. We conclude that DapE is not themain target of L-captopril inhibition in these bacteria. The methods implemented here will be useful for screening DapE-selective antimicrobial compounds directly in bacterial cultures. Copyright © 2011 N. R. Uda and M. Creus.