Antibacterial action of dipeptides containing an inhibitor of glucosamine-6-phosphate isomerase.
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.
Chmara
Henryk
H
Department of Pharmaceutical Technology & Biochemistry, Technical University of GdanAsk, 11/12 Narutowicza Str, 80-952 GdanAsk, Poland.
Milewski
Slawomir
S
Department of Pharmaceutical Technology & Biochemistry, Technical University of GdanAsk, 11/12 Narutowicza Str, 80-952 GdanAsk, Poland.
Andruszkiewicz
Ryszard
R
Department of Pharmaceutical Technology & Biochemistry, Technical University of GdanAsk, 11/12 Narutowicza Str, 80-952 GdanAsk, Poland.
Mignini
Fiorenzo
F
Department of Molecular, Animal & Cell Biology, University of Camerino, 62032 Camerino, Italy.
Borowski
Edward
E
Department of Pharmaceutical Technology & Biochemistry, Technical University of GdanAsk, 11/12 Narutowicza Str, 80-952 GdanAsk, Poland.
D019747:Aldose-Ketose Isomerases / Q000037:antagonists & inhibitors*; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology*; D001412:Bacillus subtilis / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D001433:Bacteriolysis; D001692:Biological Transport; D002473:Cell Wall / Q000378:metabolism; D004151:Dipeptides / Q000378:metabolism / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D005650:Fumarates / Q000378:metabolism / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D010457:Peptidoglycan / Q000096:biosynthesis; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D004151:Dipeptides; D004791:Enzyme Inhibitors; D005650:Fumarates; D010457:Peptidoglycan; C068215:norvalyl-N(3)-(4-methoxyfumaroyl)-2,3-diaminopropionic acid; D015091:beta-Alanine; C056276:N(3)-(4-methoxyfumaroyl)-2,3-diaminopropionic acid; C020582:glucosamine-6-phosphate isomerase; D019747:Aldose-Ketose Isomerases