ANTIBACTERIAL ACTION OF DIPEPTIDES CONTAINING AN INHIBITOR OF GLUCOSAMINE-6-PHOSPHATE ISOMERASE

Several dipeptides, containing the N-3-(4-methoxyfumaroyl)-L-2,3-diami nopropanoic acid (FMDP) moiety linked to protein and non-protein amino acids, exhibited a strong growth-inhibitory and bactericidal effect a gainst Bacillus subtilis. FMDP-dipeptides were efficiently transported into bacterial cells by a di-tripeptide permease and subsequently cle aved by intracellular Mn2+/Co2+-dependent peptidases. Cleavage rates [ 0.1-5.6 mu mol min(-1) (mg protein)(-1)] were about two orders of magn itude lower than transport rates [40-200 mu mol min(-1) (mg dry wt)(-1 )]. The released FMDP inactivated glucosamine-6-phosphate (GlcN-6-P) i somerase, an enzyme catalysing the first committed step in a biosynthe tic pathway leading to amino sugar-nucleotide precursors of bacterial peptidoglycan. Inhibition of GlcN-6-P isomerase precluded peptidoglyca n biosynthesis and resulted in a strong bacteriolytic effect. Results of the studies on consequences of GlcN-6-P isomerase inhibition upon t he action of FMDP-dipeptides provided evidence demonstrating that the lack of endogenous GlcN-6-P could be a reason for the triggering of ba cterial autolysis. Peptides containing the inhibitors of GlcN-6-P isom erase are one of the very few antimicrobial agents known that exhibit both bactericidal and fungicidal effects.