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 EN

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 against DapE in bacteria.

Since DapE knockout strains of gram-negative bacteria are viable upon chemical supplementation 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 the main 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.