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

• Published in: Microbiology (Society for General Microbiology) Vol. 144; no. 5; pp. 1349 - 1358
• Main Authors: Chmara, Henryk, Milewski, Slawomir, Andruszkiewicz, Ryszard, Mignini, Fiorenzo, Borowski, Edward
• Format: Journal Article
• Language: English
• Published: Reading Soc General Microbiol 01.05.1998; Society for General Microbiology
• Subjects: Aldose-Ketose Isomerases - antagonists & inhibitors; Anti-Bacterial Agents - metabolism; Anti-Bacterial Agents - pharmacology; Antibiotics (antibacterial agents, antifungal agents); Antibiotics, microbial producers, chemotherapic agents, antiseptics, disinfecting agents; Applied microbiology; Bacillus subtilis; Bacillus subtilis - drug effects; Bacillus subtilis - enzymology; Bacillus subtilis - metabolism; Bacteriolysis; beta-Alanine - analogs & derivatives; beta-Alanine - metabolism; beta-Alanine - pharmacology; Biological and medical sciences; Biological Transport; Cell Wall - metabolism; Dipeptides - metabolism; Dipeptides - pharmacology; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; Fumarates - metabolism; Fumarates - pharmacology; Fundamental and applied biological sciences. Psychology; Microbial Sensitivity Tests; Microbiology; Peptidoglycan - biosynthesis; Intramolecular oxidoreductases; Enzyme; Bacillus subtilis; Enzyme inhibitor; Glucosamine-6-phosphate isomerase; Biosynthesis; Bacillaceae; Cell wall; Peptidoglycan; Antifungal agent; Isomerases; Bacillales; Dipeptides; Bacteria; Antibacterial agent; Mechanism of action
• ISSN: 1350-0872; 1465-2080
• DOI: 10.1099/00221287-144-5-1349

Department of Pharmaceutical Technology & Biochemistry, Technical University of GdanAsk, 11/12 Narutowicza Str, 80-952 GdanAsk, Poland Department of Molecular, Animal & Cell Biology, University of Camerino, 62032 Camerino, Italy ABSTRACT Several dipeptides, containing the N 3 -(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 Mn 2+ /Co 2+ -dependent peptidases. Cleavage rates [0.1-5.6 µmol min -1 (mg protein) -1 ] were about two orders of magnitude lower than transport rates [40-200 µmol 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. * Author for correspondence: Slawomir Milewski. Tel: +48 58 347 21 07. Fax: +48 58 347 26 94. e-mail: milewski@altis.chem.pg.gda.pl Keywords: dipeptidies, Bacillus subtilis, cell wall