Antibacterial action of dipeptides containing an inhibitor of glucosamine-6-phosphate isomerase.

Abstract

Several dipeptides, containing the N3-(4-methoxyfumaroyl)-L-2,3-diaminopropanoic acid (FMDP) moiety linked to protein and non-protein amino acids, exhibited a strong growth-inhibitory and bactericidal effect against Bacillus subtilis. FMDP-dipeptides were efficiently transported into bacterial cells by a di-tripeptide permease and subsequently cleaved by intracellular Mn2+/Co2+-dependent peptidases. Cleavage rates [0.1-5.6 micromol min-1 (mg protein)-1] were about two orders of magnitude lower than transport rates [40-200 micromol min-1 (mg dry wt)-1]. The released FMDP inactivated glucosamine-6-phosphate (GlcN-6-P) isomerase, an enzyme catalysing the first committed step in a biosynthetic pathway leading to amino sugar-nucleotide precursors of bacterial peptidoglycan. Inhibition of GlcN-6-P isomerase precluded peptidoglycan biosynthesis and resulted in a strong bacteriolytic effect. Results of the studies on consequences of GlcN-6-P isomerase inhibition upon the action of FMDP-dipeptides provided evidence demonstrating that the lack of endogenous GlcN-6-P could be a reason for the triggering of bacterial autolysis. Peptides containing the inhibitors of GlcN-6-P isomerase are one of the very few antimicrobial agents known that exhibit both bactericidal and fungicidal effects.

• Authors: Henryk Chmara, Slawomir Milewski, Ryszard Andruszkiewicz, Fiorenzo Mignini, Edward Borowski
• Journal: Microbiology (Reading, England) (Microbiology (Reading)) Vol. 144 ( Pt 5) Pg. 1349-1358 (May 1998) ISSN: 1350-0872 [Print] England
• PMID: 9660640 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Bacterial Agents
• Dipeptides
• Enzyme Inhibitors
• Fumarates
• Peptidoglycan
• norvalyl-N(3)-(4-methoxyfumaroyl)-2,3-diaminopropionic acid
• beta-Alanine
• N(3)-(4-methoxyfumaroyl)-2,3-diaminopropionic acid
• glucosamine-6-phosphate isomerase
• Aldose-Ketose Isomerases

Topics

• Aldose-Ketose Isomerases (antagonists & inhibitors)
• Anti-Bacterial Agents (metabolism, pharmacology)
• Bacillus subtilis (drug effects, enzymology, metabolism)
• Bacteriolysis
• Biological Transport
• Cell Wall (metabolism)
• Dipeptides (metabolism, pharmacology)
• Enzyme Inhibitors (metabolism, pharmacology)
• Fumarates (metabolism, pharmacology)
• Microbial Sensitivity Tests
• Peptidoglycan (biosynthesis)
• beta-Alanine (analogs & derivatives, metabolism, pharmacology)