Structure, biochemistry and mechanism of action of glycopeptide antibiotics

  • P. E. Reynolds

Abstract

Glycopeptide antibiotics, including vancomycin and teicoplanin, are large, rigid molecules that inhibit a late stage in bacterial cell wall peptidoglycan synthesis. The three-dimensional structure contains a cleft into which peptides of highly specific configuration (L-aa-D-aa-D-aa) can fit: such sequences are found only in bacterial cell walls, hence glycopeptides are selectively toxic. Glycopeptides interact with peptides of this conformation by hydrogen bonding, forming stable complexes. As a result of binding to L-aa-D-Ala-D-Ala groups in wall intermediates, glycopeptides inhibit, apparently by steric hindrance, the formation of the backbone glycan chains (catalysed by peptidoglycan polymerase) from the simple wall subunits as they are extruded through the cytoplasmic membrane. The subsequent transpeptidation reaction that imparts rigidity to the cell wall is also thus inhibited. This unique mechanism of action, involving binding of the bulky inhibitor to the substrate outside the membrane so that the active sites of two enzymes cannot align themselves correctly, renders the acquisition of resistance to the glycopeptide antibiotics more difficult than that to the majority of the other antibiotic groups.

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References

  1. 1.
    McCormick, M. H., Stark, W. M., Pittenger, G. E., Pittenger, R. C., McGuire, J. M.: Vancomycin, a new antibiotic. I: Chemical and biologic properties. Antibiotics Annual 1956, 1955–1956: 606–611.Google Scholar
  2. 2.
    Farber, B. B. Vancomycin: renewed interest in an old drug. European Journal of Clinical Microbiology 1984, 3: 1–3.PubMedGoogle Scholar
  3. 3.
    Barna, J. C. J., Williams, D. H., Stone, D. J. M., Leung, T. W. C., Doddrell, D. M. Structure elucidation of the teicoplanin antibiotics. Journal of the American Chemical Society 1984, 106: 4895–5902.CrossRefGoogle Scholar
  4. 4.
    Somma, S., Gastaldo, L., Corti, A.: Teicoplanin, a new antibiotic fromActinoplanes teichomyceticus nov. sp. Antimicrobial Agents and Chemotherapy 1984, 26: 917–923.Google Scholar
  5. 5.
    Barna, J. C. J., Williams, D. H. The structure and mode of action of glycopeptide antibiotics of the vancomycin group. Annual Reviews of Microbiology 1984, 38: 339–357.CrossRefGoogle Scholar
  6. 6.
    Jeffs, P. W., Nisbet, L. J. Glycopeptide antibiotics: a comprehensive approach to discovery, isolation, and structure determination. In: Actor, P., Daneo-Moore, L., Higgins, M. L., Salton, M. R. J., Shockman, G. D. (ed.): Antibiotic inhibition of bacterial cell surface assembly and function. American Society for Microbiology, Washington, DC, 1988, p. 509–530.Google Scholar
  7. 7.
    Williams, D. H., Rajananda, V., Williamson, M. P., Bojesen, G. The vancomycin and ristocetin group of antibiotics. In: Sammes, P. G. (ed.): Topics in antibiotic chemistry. Horwood, Chichester, 1980, p. 119–158.Google Scholar
  8. 8.
    Coller, B. S., Gralnick, H. R. Studies on the mechanism of ristocetin-induced platelet agglutination. Effects of structural modification of ristocetin and vancomycin. Journal of Clinical Investigation 1977, 60: 302–312.PubMedGoogle Scholar
  9. 9.
    Parenti, F. Structure and mechanism of action of teicoplanin. Journal of Hospital Infection 1986, 7, Supplement A: 79–83.CrossRefPubMedGoogle Scholar
  10. 10.
    Reynolds, P. E. Studies on the mode of action of vancomycin. Biochimica et Biophysica Acta 1961, 52: 403–405.CrossRefPubMedGoogle Scholar
  11. 11.
    Jordan, D. C. Effect of vancomycin on the synthesis of the cell wall mucopeptide ofStaphylococcus aureus. Biochemical and Biophysical Research Communications 1961, 6: 167–170.CrossRefPubMedGoogle Scholar
  12. 12.
    Perkins, H. R., Nieto, M. The preparation of iodinated vancomycin and its distribution in bacteria treated with the antibiotic. Biochemical Journal 1970, 116: 83–92.PubMedGoogle Scholar
  13. 13.
    Jordan, D. C., Reynolds, P. E. Vancomycin. In: Corcoran, J. W., Hahn, F. E. (ed.): Antibiotics, volume III. Mechanism of action of antimicrobial and antitumor agents. Springer-Verlag, Berlin, 1974, p. 704–718.Google Scholar
  14. 14.
    Chatterjee, A. N., Perkins, H. R. Compounds formed between nucleotides related to the biosynthesis of bacterial cell wall and vancomycin. Biochemical and Biophysical Research Communications 1966, 24: 489–494.CrossRefPubMedGoogle Scholar
  15. 15.
    Perkins, H. R. Specificity of combination between mucopeptide precursors and vancomycin or ristocetin. Biochemical Journal 1969, 111: 195–205.PubMedGoogle Scholar
  16. 16.
    Nieto, M., Perkins, H. R. Modifications of the acyl-D-alanyl-D-alanine terminus affecting complex formation with vancomycin. Biochemical Journal 1971, 123: 789–803.PubMedGoogle Scholar
  17. 17.
    Reynolds, P. E. Antibiotics affecting cell wall synthesis. In: Newton, B. A., Reynolds, P. E. (ed.): Biochemical studies of antimicrobial drugs. Symposium of the Society for General Microbiology 1966, 16: 47–69.Google Scholar
  18. 18.
    Jordan, D. C. Effect of vancomycin on the synthesis of the cell wall and cytoplasmic membrane ofStaphylococcus aureus. Canadian Journal of Microbiology 1965, 11: 390–393.PubMedGoogle Scholar
  19. 19.
    Perkins, H. R. Vancomycin and related antibiotics. Pharmacology and Therapeutics 1982, 16: 181–197.CrossRefPubMedGoogle Scholar
  20. 20.
    Nieto, M., Perkins, H. R., Reynolds, P. E. Reversal by a specific peptide (diacetyl--L-diaminobutyryl-D-alanyl-D-alanine) of vancomycin inhibition in intact bacteria and cell-free preparations. Biochemical Journal 1972, 126: 139–149.PubMedGoogle Scholar
  21. 21.
    Sheldrick, G. M., Jones, P. G., Kennard, O., Williams, D. H., Smith, G. A. Structure of vancomycin and its complex with acetyl-D-alanyl-D-alanine. Nature 1978, 271: 223–225.PubMedGoogle Scholar
  22. 22.
    Reynolds, P. E. Inhibitors of bacterial cell wall synthesis. In: Greenwood, D., O'Grady, F. (ed.): The scientific basis of antimicrobial chemotherapy. Symposium of the Society for General Microbiology 1985, 38: 13–40.Google Scholar
  23. 23.
    Moore, E. P., Speller, D. C. E. In vitro teicoplanin resistance in coagulase-negative staphylococci from patients with endocarditis and from a cardiac surgery unit. Journal of Antimicrobial Chemotherapy 1988, 21: 417–424.PubMedGoogle Scholar
  24. 24.
    Uttley, A. H. C., Collins, C. H., Naidoo, J., George, R. C. Vancomycin-resistant enterococci. Lancet 1988, i: 57–58.CrossRefGoogle Scholar
  25. 25.
    Leclercq, R., Derlot, E., Duval, J., Courvalin, P. Plasmid-mediated resistance to vancomycin and teicoplanin inEnterococcus faecium. New England Journal of Medicine 1988, 319: 157–161.PubMedGoogle Scholar
  26. 26.
    Schlaes, D. M., Bouvet, A., Devine, C., Schlaes, J. H., Al-Obeid, S., Williamson, R. Inducible, transferable resistance to vancomycin inEnterococcus faecalis A256. Antimicrobial Agents and Chemotherapy 1989, 33: 198–203.PubMedGoogle Scholar
  27. 27.
    Park, W., Matsuhashi, M. Staphylococcus aureus andMicrococcus luteus peptidogly can transglycosylases that are not penicillin-binding proteins. Journal of Bacteriology 1984, 157: 538–544.PubMedGoogle Scholar

Copyright information

© Friedr. Vieweg & Sohn Verlagsgesellschaft MbH 1989

Authors and Affiliations

  • P. E. Reynolds
    • 1
  1. 1.Department of BiochemistryUniversity of CambridgeCambridgeUK

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