1887

Abstract

Moenomycin is a natural product glycolipid that inhibits the growth of a broad spectrum of Gram-positive bacteria. In , moenomycin inhibits peptidoglycan synthesis at the transglycosylation stage, causes accumulation of cell-wall intermediates, and leads to lysis and cell death. However, unlike , where 5–6 log units of killing are observed, 0–2 log units of killing occurred when Gram-positive bacteria were treated with similar multiples of the MIC. In addition, bulk peptidoglycan synthesis in intact Gram-positive cells was resistant to the effects of moenomycin. In contrast, synthetic disaccharides based on the moenomycin disaccharide core structure were identified that were bactericidal to Gram-positive bacteria, inhibited cell-wall synthesis in intact cells, and were active on both sensitive and vancomycin-resistant enterococci. These disaccharide analogues do not inhibit the formation of -acetylglucosamine-β-1,4-MurNAc-pentapeptide-pyrophosphoryl-undecaprenol (lipid II), but do inhibit the polymerization of lipid II into peptidoglycan in . In addition, cell growth was required for bactericidal activity. The data indicate that synthetic disaccharide analogues of moenomycin inhibit cell-wall synthesis at the transglycosylation stage, and that their activity on Gram-positive bacteria differs from moenomycin due to differential targeting of the transglycosylation process. Inhibition of the transglycosylation process represents a promising approach to the design of new antibacterial agents active on drug-resistant bacteria.

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2000-12-01
2024-12-13
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References

  1. Adam M., Fraipont C., Rhazi N.8 other authors 1997; The bimolecular G57-V577 polypeptide chain of the class B penicillin-binding protein 3 of Escherichia coli catalyzes peptide bond formation from thiolesters and does not catalyze glycan chain polymerization from the lipid II intermediate. J Bacteriol 179:6005–6009
    [Google Scholar]
  2. Allen N. E., Hobbs J. N. Jr, Richardson J. M., Riggin R. M. 1992; Biosynthesis of modified peptidoglycan precursors by vancomycin-resistant Enterococcus faecium. FEMS Microbiol Lett 77:109–115
    [Google Scholar]
  3. Allen N. E., Hobbs J. N. Jr, Nicas T. I. 1996; Inhibition of peptidoglycan biosynthesis in vancomycin-susceptible and-resistant bacteria by a semisynthetic glycopeptide antibiotic. Antimicrob Agents Chemother 40:2356–2362
    [Google Scholar]
  4. Anderson J. S., Meadow P. M., Haskin M. A., Strominger J. L. 1966; Biosynthesis of the peptidoglycan of bacterial cell walls. I. Utilization of uridine diphosphate acetylmuramyl pentapeptide and uridine diphosphate acetylglucosamine for peptidoglycan synthesis by particulate enzymes from Staphylococcus aureus and Micrococcus lysodeikticus. Arch Biochem Biophys 116:487–515 [CrossRef]
    [Google Scholar]
  5. Billot-Klein D., Shlaes D., Bryant D., Bell D., Legrand R., Gutmann L., van Heijenoort J. 1997; Presence of UDP-N-acetylmuramyl-hexapeptides and -heptapeptides in enterococci and staphylococci after treatment with ramoplanin, tunicamycin, or vancomycin. J Bacteriol 179:4684–4688
    [Google Scholar]
  6. Branstrom A. A., Midha S., Goldman R. C. 2000a; In situ assay for identifying inhibitors of bacterial transglycosylase. FEMS Microbiol Lett 191:187–190 [CrossRef]
    [Google Scholar]
  7. Branstrom A. A., Midha S., Longley C. B., Han K., Baizman E. R., Axelrod H. R. 2000b; Assay for identification of inhibitors specific for bacterial MraY translocase and MurG transferase. Anal Biochem 280:315–319 [CrossRef]
    [Google Scholar]
  8. Di Berardino M., Dijkstra A., Stuber D., Keck W., Gubler M. 1996; The monofunctional glycosyltransferase of Escherichia coli is a member of a new class of peptidoglycan-synthesising enzymes. FEBS Lett 392:184–188 [CrossRef]
    [Google Scholar]
  9. El-Abadla N., Lampilis M., Hennig L., Findeisen M., Welzel P., Muller D., Markus A., van Heijenoort J. 1999; Moenomycin A: the role of the methyl group in the moenuronamide unit and a general discussion of structure-activity relationships. Tetrahedron 55:699–722 [CrossRef]
    [Google Scholar]
  10. Frost D. J., Brandt K., Capobianco J., Goldman R. 1994; Characterization of (1,3)-β-glucan synthase in Candida albicans: microsomal assay from the yeast or mycelial morphological forms and a permeabilized whole-cell assay. Microbiology 140:2239–2246 [CrossRef]
    [Google Scholar]
  11. Ge M., Chen Z., Onishi H. R., Kohler J., Silver L. L., Kerns R., Fukuzawa S., Thompson C., Kahne D. 1999; Vancomycin derivatives that inhibit peptidoglycan biosynthesis without binding d-Ala-d-Ala. Science 284:507–511 [CrossRef]
    [Google Scholar]
  12. Goffin C., Ghuysen J.-M. 1998; Multimodular penicillin-binding proteins: an enigmatic family of orthologs and paralogs. Microbiol Mol Biol Rev 62:1079–1093
    [Google Scholar]
  13. Goldman R. C., Frost D. J., Capobianco J. O., Kadam S., Rasmussen R. R., Abad-Zapatero C. 1995; Antifungal drug targets: Candida secreted aspartyl protease and fungal wall beta-glucan synthesis. Infect Agents Dis 4:228–247
    [Google Scholar]
  14. Hara H., Suzuki H. 1984; A novel glycan polymerase that synthesizes uncross-linked peptidoglycan in Escherichia coli. FEBS Lett 168:155–160 [CrossRef]
    [Google Scholar]
  15. van Heijenoort Y., van Heijenoort J. 1980; Biosynthesis of the peptidoglycan of Escherichia coli K-12: properties of the in vitro polymerization by transglycosylation. FEBS Lett 110:241–244 [CrossRef]
    [Google Scholar]
  16. van Heijenoort Y., Derrien M., van Heijenoort J. 1978; Polymerization by transglycosylation in the biosynthesis of the peptidoglycan of Escherichia coli K-12 and its inhibition by antibiotics. FEBS Lett 89:141–144 [CrossRef]
    [Google Scholar]
  17. van Heijenoort Y., Leduc M., Singer H., van Heijenoort J. 1987; Effects of moenomycin on Escherichia coli. J Gen Microbiol 133:667–674
    [Google Scholar]
  18. van Heijenoort Y., Gomez M., Derrien M., Ayala J., van Heijenoort J. 1992; Membrane intermediates in the peptidoglycan metabolism of Escherichia coli: possible roles of PBP 1b and PBP 3. J Bacteriol 174:3549–3557
    [Google Scholar]
  19. Holtje J. V. 1996a; A hypothetical holoenzyme involved in the replication of the murein sacculus of Escherichia coli. Microbiology 142:1911–1918 [CrossRef]
    [Google Scholar]
  20. Holtje J. V. 1996b; Molecular interplay of murein synthases and murein hydrolases in Escherichia coli. Microb Drug Resist 2:99–103 [CrossRef]
    [Google Scholar]
  21. Holtje J. V. 1998; Growth of the stress-bearing and shape-maintaining murein sacculus of Escherichia coli. Microbiol Mol Biol Rev 62:181–203
    [Google Scholar]
  22. Huber G. 1979; Moenomycin and related phosphorus-containing antibiotics. In Antibiotics vol. 5 part 1, p. 135Edited by Hahn F. E. New York: Springer;
    [Google Scholar]
  23. Ikeda M., Wachi M., Matsuhashi M. 1992; The murG gene of the Escherichia coli chromosome encoding UDP-N-acetylglucosamine: undecaprenyl-pyrophosphoryl-N-acetylmuramoyl-pentapeptide N-acetylglucosaminyl transferase. J Gen Appl Microbiol 38:53–62 [CrossRef]
    [Google Scholar]
  24. Ishino F., Matsuhashi M. 1981; Peptidoglycan synthetic enzyme activities of highly purified penicillin-binding protein 3 in Escherichia coli: a septum-forming reaction sequence. Biochem Biophys Res Commun 101:905–911 [CrossRef]
    [Google Scholar]
  25. Kakarla R., Ghosh M., Anderson J. A., Dulina R. G., Sofia M. J. 1999; Expeditious route to F unit building blocks of moenomycin A. Tetrahedron Lett 40:5–8 [CrossRef]
    [Google Scholar]
  26. Ko Y. T., Frost D. J., Ho C. T., Ludescher R. D., Wasserman B. P. 1994; Inhibition of yeast (1,3)-β-glucan synthase by phospholipase A2 and its reaction products. Biochim Biophys Acta 1193:31–40 [CrossRef]
    [Google Scholar]
  27. Koch A. L. 1998; The three-for-one model for gram-negative wall growth: a problem and a possible solution. FEMS Microbiol Lett 162:127–134 [CrossRef]
    [Google Scholar]
  28. Kohlrausch U., Holtje J. V. 1991a; Analysis of murein and murein precursors during antibiotic-induced lysis of Escherichia coli. J Bacteriol 173:3425–3431
    [Google Scholar]
  29. Kohlrausch U., Holtje J. V. 1991b; One-step purification procedure for UDP-N-acetylmuramyl-peptide murein precursors from Bacillus cereus. FEMS Microbiol Lett 62:253–257
    [Google Scholar]
  30. Lai M. H., Kirsch D. R. 1996; Induction signals for vancomycin resistance encoded by the vanA gene cluster in Enterococcus faecium. Antimicrob Agents Chemother 40:1645–1648
    [Google Scholar]
  31. Mani N., Sancheti P., Jiang Z. D.8 other authors 1998; Screening systems for detecting inhibitors of cell wall transglycosylation in Enterococcus: cell wall transglycosylation inhibitors in Enterococcus. J Antibiot 51:471–479 [CrossRef]
    [Google Scholar]
  32. Matsuhashi M., Ishino F., Nakagawa J., Mitsui K., Nakajima-Iijima S., Tamaki S. 1981; Enzymatic activities of penicillin-binding protiens of Escherichia coli and their sensitivities to β-lactam antibiotics. In β-Lactam Antibiotics pp. 169–184Edited by Salton M., Shockman G. D. New York: Academic Press;
    [Google Scholar]
  33. Men H., Park P., Ge M., Walker S. 1998; Substrate synthesis and activity assay for MurG. J Am Chem Soc 120:2484–2485 [CrossRef]
    [Google Scholar]
  34. Mirelman D., Yashouv-Gan Y., Schwarz U. 1976; Peptidoglycan biosynthesis in a thermosensitive division mutant of Escherichia coli. Biochemistry 15:1781–1790 [CrossRef]
    [Google Scholar]
  35. Park W., Matsuhashi M. 1984; Staphylococcus aureus and Micrococcus luteus peptidoglycan transglycosylases that are not penicillin-binding proteins. J Bacteriol 157:538–544
    [Google Scholar]
  36. von Rechenberg M., Ursinus A., Holtje J. V. 1996; Affinity chromatography as a means to study multienzyme complexes involved in murein synthesis. Microb Drug Resist 2:155–157 [CrossRef]
    [Google Scholar]
  37. Sampson B. A., Misra R., Benson S. A. 1989; Identification and characterization of a new gene of Escherichia coli K-12 involved in outer membrane permeability. Genetics 122:491–501
    [Google Scholar]
  38. Schiffer G., Holtje J.-V. 1999; Cloning and characterization of PBP 1C, a third member of the multimodular class A penicillin-binding proteins of Escherichia coli. J Biol Chem 274:32031–32039 [CrossRef]
    [Google Scholar]
  39. Sofia M. J., Allanson N., Hatzenbuhler N.23 other authors 1999; Discovery of novel disaccharide antibacterial agents using a combinatorial library approach. J Med Chem 42:3193–3198 [CrossRef]
    [Google Scholar]
  40. Tamura T., Suzuki H., Nishimura Y., Mizoguchi J., Hirota Y. 1980; On the process of cellular division in Escherichia coli: isolation and characterization of penicillin-binding proteins 1a, 1b, and 3. Proc Natl Acad Sci USA 77:4499–4503 [CrossRef]
    [Google Scholar]
  41. Vollmer W., von Rechenberg M., Holtje J. V. 1999; Demonstration of molecular interactions between the murein polymerase PBP1B, the lytic transglycosylase MltA, and the scaffolding protein MipA of Escherichia coli. J Biol Chem 274:6726–6734 [CrossRef]
    [Google Scholar]
  42. Vosberg H. P., Hoffmann-Berling H. 1971; DNA synthesis in nucleotide-permeable Escherichia coli cells. I. Preparation and properties of ether-treated cells. J Mol Biol 58:739–753 [CrossRef]
    [Google Scholar]
  43. von Wasielewski E., Muschaweck R., Schutze E. 1965; Moenomycin, a new antibiotic. 3. Biological properties. Antimicrob Agents Chemother 5:743–748
    [Google Scholar]
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