1887

Abstract

Several dipeptides, containing the -(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 FMDP-dipeptides were efficiently transported into bacterial cells by a di-tripeptide permease and subsequently cleaved by intracellular Mn/Co-dependent peptidases. Cleavage rates [0.1-5.6 μmol min (mg protein)] were about two orders of magnitude lower than transport rates [40-200 μmol min (mg dry wt)]. 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.

Loading

Article metrics loading...

/content/journal/micro/10.1099/00221287-144-5-1349
1998-05-01
2024-03-29
Loading full text...

Full text loading...

/deliver/fulltext/micro/144/5/mic-144-5-1349.html?itemId=/content/journal/micro/10.1099/00221287-144-5-1349&mimeType=html&fmt=ahah

References

  1. Andruszkiewicz, R., Chmara, H., Milewski, S., Borowski, E. (1986); Synthesis of N3-fumaramoyl-L-2,3-diaminopropanoic acid analogues, the irreversible inhibitors of glucosamine synthetase.. Int J Pept Protein Res 27:(5)449–453 [View Article]
    [Google Scholar]
  2. Andruszkiewicz, R., Chmara, H., Milewski, S., Borowski, E. (1987); Synthesis and biological properties of N3-(4-methoxy- fumaroyl)-L-2,3-diaminopropanoic acid dipeptides, a novel group of antimicrobial agents.. Journal of Medicinal Chemistry 30:(10)1715–1719 [View Article]
    [Google Scholar]
  3. Andruszkiewicz, R., Milewski, S., Zieniawa, T., Borowski, E. (1990); Anticandidal properties of N3-(4-methoxyfumaroyl)-L- 2,3-diaminopropanoic acid oligopeptides.. Journal of Medicinal Chemistry 33:(1)132–135 [View Article]
    [Google Scholar]
  4. Anraku, Y. (1980) Transport and utilisation of amino acids bacteria.. Edited by Payne, J. W. Microorganisms and Nitrogen Sources. Chichester:: Wiley,;9–33
    [Google Scholar]
  5. Atherton, F. R., Hall, M. J., Hassal, C. S., Lambert, R. W., Lloyd W.J., Ringrose P. S. (1979); Phosphonopeptides as antibacterial agents: mechanism of action of alaphosphin.. Antimicrob Agents Chemother 15:(5)696–705 [View Article]
    [Google Scholar]
  6. Atherton, F. R., Hall M.J., Hassal, C. S., Lambert, R. W., Lloyd, W. J., Ringrose P. S., Westmacott D. (1982); Antibacterial activity and mechanism of action of phosphonopeptides based on aminomethylphosphonic acid.. Antimicrob Agents Chemother 22:(4)571–578 [View Article]
    [Google Scholar]
  7. Badet, B., Vermoote, P., Haumont, P. Y., Lederer, F., LeGoffic, F. (1987); Glucosamine synthetase from Escherichia coli: purification, properties and glutamine-utilizing site location.. Biochemistry 26:(7)1940–1948 [View Article]
    [Google Scholar]
  8. Bauman, R. J., Bohme, E. H., Wiseman, J. S., Vaal, M., Nichols, J. S. (1988); Inhibition of Escherichia coli growth and diamino- pimelic acid epimerase by 3-chlorodiaminopimelic acid.. Journal of Biological Chemistry 263:(3)1119–1123 [View Article]
    [Google Scholar]
  9. Berges, D. A., de Wolf, W. E., Dunn G. L., Newman D. J., Schmidt, S. J., Taggart, J. J., Gilvarg, Ch. (1986); Studies on the active site of succinyl-CoA: tetrahydropicolinate N-succinyl transferase.. Journal of Biological Chemistry 261:(14)6160–6167 [View Article]
    [Google Scholar]
  10. Boisvert, W., Cheung, K. S., Lerner, S. A., Johnston, M. (1986); Mechanism of action of chloroalanyl antibacterial peptides.. Journal of Biological Chemistry 261:(17)7871–7878 [View Article]
    [Google Scholar]
  11. Bradford, M. M. (1976); A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding.. Analytical Biochemistry 72:(1–2)248–254 [View Article]
    [Google Scholar]
  12. Chmara, H., Andruszkiewicz, R., Borowski, E. (1986); Inactivation of glucosamine-6-phosphate synthase from Salmonella typhimurium LT2 by fumaroyl diaminopropanoic acid derivatives, a novel group of glutamine analogs.. Biochimica Et Biophysica Acta 870:(2)357–366 [View Article]
    [Google Scholar]
  13. Coggin, J. H., Martin, W. R. (1965); 6-Diazo-5-oxo-L-norleucine inhibition of Escherichia coli.. Journal of Bacteriology 89:(5)1348–1353 [View Article]
    [Google Scholar]
  14. Desmond, E. P., Starnes, W. L., Behai, F. J. (1975); Aminopeptidases of Bacillus subtilis.. Journal of Bacteriology 124:(1)353–363 [View Article]
    [Google Scholar]
  15. Dixon, M., Webb, E. C. (1979) The Enzymes. London:: Longman Group;
    [Google Scholar]
  16. Doi, E., Shibata, D., Matoba, T. (1981); Modified colorimetric ninhydrin methods for peptidase assay.. Analytical Biochemistry 118:(1)173–184 [View Article]
    [Google Scholar]
  17. Freese, E. B., Cole, R. M., Klofat, W., Freese, E. (1970); Growth, sporulation and enzyme defects of glucosamine mutants of Bacillus subtilis.. Journal of Bacteriology 101:(3)1046–1062 [View Article]
    [Google Scholar]
  18. Girodeau, J. M., Agouridas, C., Masson M., Pineau R., Le Goffic F. (1986); The lysine pathway as a target for a new genera of synthetic antibacterial antibiotics ?. ] Med Chem 29,1023—1030.
  19. Kahan, F. M., Kahan, J. S., Cassidy, P. J., Krop, H. (1974); The mechanism of action of fosfomycin.. 11th Oeso World Conference: Reflux Disease 235:364–370
    [Google Scholar]
  20. Kenig, M., Vandamme, E., Abraham, E. P. (1976); The mode of action of bacilysin and anticapsin and biochemical properties of bacilysin-resistant mutants.. Journal of General Microbiology 94:(1)46–54 [View Article]
    [Google Scholar]
  21. Kitano, K., Tomasz, A. (1979); Triggering of autolytic cell wall degradation in Escherichia coli by /f-lactam antibiotics.. Antimicrob Agents Chemother 16:(6)838–848 [View Article]
    [Google Scholar]
  22. Kucharczyk, N., Denisot, M.-A., LeGoffic, F., Badet, B. (1990); Glucosamine-6-phosphate synthase from Escherichia coli: determination of the mechanism of inactivation by N3-fumaroyl-L- 2,3-diaminopropionic derivatives.. Biochemistry 29:(15)3668–3676 [View Article]
    [Google Scholar]
  23. Laemmli, U. K. (1970); Cleavage of structural proteins during the assembly of the head of bacteriophage T4.. Nature 227:(5259)680–685 [View Article]
    [Google Scholar]
  24. Lugtenberg, E. J. J., de Haas-Menger, L., Ruyters, W. H. M. (1972); Murein synthesis and identification of cell wall precursors in temperature-sensitive lysis mutants of Escherichia coli.. Journal of Bacteriology 109:(1)326–335 [View Article]
    [Google Scholar]
  25. McCarthy, P. J., Newman, D. J., Nisbet, L. J., Kingsbury, W. (1985); Relative rates of transport of peptidyl drugs by Candida albicans.. Antimicrob Agents Chemother 28:(4)494–499 [View Article]
    [Google Scholar]
  26. Mathiopoulos, C., Mueller, J. P., Slack, F. J., Murphy, C. G., Patankar, S. et al. (1991); A Bacillus subtilis dipeptide transport system expressed during early sporulation.. Molecular Microbiology 5:(8)1903–1913 [View Article]
    [Google Scholar]
  27. Milewski, S., Chmara, H., Andruszkiewicz, R., Borowski, E. (1985); Synthetic derivatives of N3-fumaroyl-L-2,3-diaminopro- panoic acid inactivate glucosamine synthase from Candida albicans.. Biocbim Biophys Acta 828:(3)247–254 [View Article]
    [Google Scholar]
  28. Milewski, S., Andruszkiewicz, R., Borowski, E. (1988); Substrate specificity of peptide permeases in Candida albicans.. Fems Microbiology Letters 50:(1)73–78 [View Article]
    [Google Scholar]
  29. Milewski, S., Andruszkiewicz, R., Kasprzak, L., Mazerski, J., Mignini, F. et al. (1991); Mechanism of action of anticandidal dipeptides containing inhibitors of glucosamine-6- phosphate synthase.. Antimicrob Agents Chemotber 35:47–53
    [Google Scholar]
  30. Neuhaus, F. C., Hammes W. P. (1981); Inhibition of cell wall biosynthesis by analogues of alanine.. Phamacol Ther 14:(3)265–319 [View Article]
    [Google Scholar]
  31. Payne, J. W. (1972); The characterisation of dipeptidases from Escherichia coli.. Journal of General Microbiology 71:(2)267–279 [View Article]
    [Google Scholar]
  32. Payne, J. W. (1980) Transport and utilisation of peptides by bacteria.. Edited by Payne, J. W. Microorganisms and Nitrogen Sources. Chichester:: Wiley,;211–256
    [Google Scholar]
  33. Penefsky, H. S. (1977); Binding of Pt to beef heart mitochondrial ATP-ase.. Journal of Biological Chemistry 252:(9)2891–2899 [View Article]
    [Google Scholar]
  34. Perego, M., Higgins, C. F., Pearce, S. R., Gallagher, M. P., Hoch, J. A. (1991); The oligopeptide transport system of Bacillus subtilis plays a role in the initiation of sporulation.. Molecular Microbiology 5:(1)173–185 [View Article]
    [Google Scholar]
  35. Rogers, H. J., Forsberg C. W. (1971); Role of autolysins in the killing of bacteria by some bactericidal antibiotics.. Journal of Bacteriology 108:(3)1235–1243 [View Article]
    [Google Scholar]
  36. Tomasz, A. (1979); The mechanism of irreversible antimicrobial effects of penicillin.. Annual Review of Microbiology 33:(1)113–137 [View Article]
    [Google Scholar]
  37. Ward, J. B. (1975); Peptidoglycan synthesis of L-phase variants of Bacillus licheniformis and Bacillus subtilis.. Journal of Bacteriology 124:(2)668–678 [View Article]
    [Google Scholar]
  38. Warren, L. (1972) The biosynthesis and metabolism of amino sugars and amino sugar-containing heterosaccharide.. Edited by Gottschalk, A. Glycoproteins. Amsterdam:: Elsevier,;1097–1126
    [Google Scholar]
  39. Vo-Quang, Y., Carniato, D., Vo-Quang, L., Lacoste, A. M., Nenzil, E., LeGoffic F. (1986); (jS-chloro-a-aminoethyl)-Phosphonic acids as inhibitors of alanine racemase and D-alanine: D-alanine ligase.. ] Med Chem 26:(1)148–151 [View Article]
    [Google Scholar]
  40. Zalkin, H. (1993); The amidotransferases.. Adv Enzymol Relat Areas Mol Biol 66:203–309
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/micro/10.1099/00221287-144-5-1349
Loading
/content/journal/micro/10.1099/00221287-144-5-1349
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error