Skip to main content
SpringerLink
Log in

The Molecular Basis for the Mode of Action of Beta-Lactam Antibiotics and Mechanisms of Resistance

  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

This review on the molecular basis for the mode of action of β-lactam antibiotics and mechanisms of resistance is divided into three main sections. Firstly, a brief introduction to the β-lactam antibiotic family is presented from the standpoint of their natural product origins. The second section is concerned with bacterial cell wall structure and biosynthesis, and the mode of action of β-lactam antibiotics. It includes an attempted rationalization of the multiple enzyme targets of penicillin, the so-called “penicillin binding proteins”, into one or two lethal sites of action and the interaction of these enzymes with β-lactams in terms of their analogy to the natural substrate and to the substrate-enzyme transition state. The final part covers the phenomenon of bacterial resistance to β-lactam antibiotic therapy and deals with the two most important manifestations of resistance; permeability and the production of β-lactamases. This latter more crucial factor is then expanded with particular reference to the irreversible inhibition of these enzymes by suicide inactivators; a general theory for irreversible β-lactamase inhibition is discussed and the future prospects within this whole area are briefly overviewed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Fleming, A. (1929). Br. J. Exp. Path. 10, 226–236.

    Google Scholar 

  2. Morin, R. B., Gorman, M., eds. (1982) “Chemistry and Biology of Beta-Lactam Antibiotics” Academic Press, London.

    Google Scholar 

  3. Brown, A. G. (1982) J. Antimicrob. Chemother. 10, 365–368.

    Google Scholar 

  4. Nagarayan, R., Boeck, L. D., Gorman, M., Hamill, R. L., Higgens, C. E., Hoehn, M. M., Stark, W. W., Whitney, J. G. (1971) J. Am. Chem. Soc. 93, 2308–2310.

    Google Scholar 

  5. Narisada, M., Yoshida, T., Onoue, H., Ohtani, M., Okada, T., Tsuji, T., Kikkawa, I., Haga, N., Satoh, H., Itani, H., Nagata, W. (1979) J. Med. Chem. 22, 757.

    Google Scholar 

  6. Slocombe, B., Basker, M. J., Bentley, P. H., Clayton, J. P., Cole, M., Comber, K. R., Dixon, R. A., Edmondson, R. A., Jackson, D., Merrikin, D. J., Sutherland, R. (1981) Antimicrob. Agents Chemother. 20, 38–46.

    Google Scholar 

  7. Albers-Schoenberg, G., Arison, B. H., Hensens, O. D., Hirshfield, J., Hoogsteen, K., Kaczka, E. A., Rhodes, R. E., Kahan, J. S., Kahan, F. M., Ratcliffe, R. W., Walton, E., Ruswinkle, L. J., Morin, R. B., Christensen, B. G. (1978) J. Am. Chem. Soc. 100, 6491–6499.

    Google Scholar 

  8. Brown, A. G., Corbett, D. F., Eglington, A. J., Howarth, T. T. (1977) J. Chem. Soc. Chem. Commun. 523–525.

  9. Okamura, K., Hirata, S., Okumura, Y., Fukagawa, Y., Shimauchi, Y., Kouno, K., Ishikura, T., Lein, J. (1978) J. Antibiotics 31, 480–482.

    Google Scholar 

  10. Tanaka, K., Shoji, J., Terui, Y., Tsuji, N., Kondo, E., Mayama, M., Kawamura, Y., Hattori, T., Matsumoto, K., Yoshida, T. (1981) J. Antibiotics 34, 909–911.

    Google Scholar 

  11. Kropp, H., Sundelof, J. G., Hadju, R., Kahan, F. M. (1982) Antimicrob. Agents Chemother. 22, 62–70.

    Google Scholar 

  12. Kahan, F. M., Kropp, H.; Sundelof, J. G.; Birnbaum, J. (1983) J. Antimicrob. Chemother. 12, Supplement D, 1–36.

    Google Scholar 

  13. Cama, L. D., Christensen, B. G. (1978) J. Am. Chem. Soc. 100, 8006–8007.

    Google Scholar 

  14. Marier, R. L., McCloskey, R. V., Dickenson, G., Sanders, C. V., Aldridge, K. E., Hoffman, T., Gutterman, D.; Janney, A. (1983) J. Antimicrob. Chemother. 12, Supplement D, 133–140.

    Google Scholar 

  15. Ratcliffe, R. W., Albers-Schoenberg, G. (1982) Reference 2, Vol. 2, 276–310.

  16. Aoki, H.; Sakai; H., Kohsaka, M., Konomi, T., Hosoda, J., Kubochi, Y., Iguchi, E., Imanaka, H. (1976) J. Antibiotics 29, 492–500.

    Google Scholar 

  17. Imada, A., Kitano, K., Kintaka, K., Muroi, M., Asai, M. (1981) Nature 289, 590–591.

    Google Scholar 

  18. Sykes, R. B., Cimarusti, C. M., Bonner, D. P., Bush, K., Floyd, D. M., Georgopapadakou, N. H., Koster, W. H., Liu, W. C., Parker, W. L., Principe, P. A., Rathnum, M. L., Slusarchyk, W. A., Trejo, W. H., Wells, J. S. (1981) Nature 291, 489–491.

    Google Scholar 

  19. Sykes, R. B., Bonner, D. P., Bush, K., Georgopapadakou, N. H. (1982) Antimicrob. Agents Chemother. 21, 85–92.

    Google Scholar 

  20. Koster, W. H., Cimarusti, C. M., Sykes, R. B. (1982) Ref. 2, Vol. 3, 357–368.

  21. Gardner, A. D. (1940) Nature 146, 837–838.

    Google Scholar 

  22. Duguid, J. P. (1946) Edinburgh Med. J. 53, 401–412.

    Google Scholar 

  23. Park, J. T., Johnson, M. J. (1948) J. Biol. Chem. 179, 585–592.

    Google Scholar 

  24. Park, J. T. (1952) J. Biol. Chem. 194, 897–904.

    Google Scholar 

  25. Park, J. T., Strominger, J. L. (1957) Science 125, 99–101.

    Google Scholar 

  26. Ghuysen, J.-M. (1977) Cell Surfaces Rev. 4, 463–595.

    Google Scholar 

  27. Tipper, D. J., Wright, A. (1979) in The Bacteria (Sokatch, J. R., Ornston, L. N. eds.), Vol. 7, 291–426, Academic Press, N. Y.

    Google Scholar 

  28. Mirelman, D. (1979) in Bacterial Outer Membranes: Biosynthesis and Functions (Inouye, M., ed.) 115–166, Wiley and Sons, N.Y.

    Google Scholar 

  29. Suginaka, H., Blumberg, P. M., Strominger, J. L. (1972) J. Biol. Chem. 247, 5279–5288.

    Google Scholar 

  30. Spratt, B. G. (1977) Eur. J. Biochem. 72, 341–352.

    Google Scholar 

  31. Spratt, B. G. (1980) Phil. Trans. R. Soc. Lond. Ser. B. 289, 273–288.

    Google Scholar 

  32. Amanuma, H., Strominger, J. L. (1980) J. Biol. Chem. 255, 1173–1180.

    Google Scholar 

  33. Lund, F., Tybring, L. (1972) Nature 236, 135–137.

    Google Scholar 

  34. Tybring, L., Melchior, N. H. (1975) Antimicrob. Agents Chemother. 8, 271–276.

    Google Scholar 

  35. Howarth, T. T., Brown, A. G., King, T. J. (1976) J. Chem. Soc. Chem. Commun. 266–267.

  36. Blumberg, P. M., Strominger, J. L. (1974) Bacteriol. Rev. 38, 291–335.

    Google Scholar 

  37. Waxman, D. S., Strominger, J. L. (1982) Reference 2, Vol. 3, 209–285.

  38. Ghuysen, J.-M. (1980) in Topics in Antibiotic Chemistry (Sammes, P. G., ed.), Vol. 5, 9–117, Wiley and Sons, N. Y.

    Google Scholar 

  39. Blumberg, P. M., Strominger, J. L. (1971) Proc. Nat. Acad. Sci. USA 68, 2814–2817.

    Google Scholar 

  40. Tomasz, A. (1979) Ann. Rev. Microbiol. 33, 113–137.

    Google Scholar 

  41. Tipper, D. J., Strominger, J. L. (1965) Proc. Nat. Acad. Sci. USA 54, 1133.

    Google Scholar 

  42. Waxman, D. J., Strominger, J. L. (1980) J. Biol. Chem. 255, 3964–3976.

    Google Scholar 

  43. Kozarich, J. W., Nishino, T.; Willoughby, E., Strominger, J. L. (1977) J. Biol. Chem. 252, 7525–7529.

    Google Scholar 

  44. Georgopapadakou, N., Hammarstrom, S., Strominger, J. L. (1977) Proc. Nat. Acad. Sci. USA 74, 1009–1012.

    Google Scholar 

  45. Stietz, T. A., Shulmann, R. G. (1982) Ann. Review. Biophys. Bioeng. 11, (Mullins, L. J., ed.), 419–444, Annual Reviews Inc. Palo Alto.

    Google Scholar 

  46. Boyd, D. B. (1981) Reference 2, Vol. 1, 437–545.

  47. Sweet, R. (1972) in Cephalosporins and Penicillins: Chemistry and Biology (Flynn, E. H., ed.), 280–309, Academic Press, London.

    Google Scholar 

  48. Morin, R. B., Jackson, B. G., Mueller, R. A., Lavagnino, E. R., Scanlon, W. B., Andrews, S. L. (1969), J. Am. Chem. Soc. 91, 1401–1407.

    Google Scholar 

  49. Boehme, E. H. W., Applegate, H. E., Toeplitz, B., Dolfini, J. E., Gougoutas, J. Z. (1971) J. Am. Chem. Soc. 93, 4324–4326.

    Google Scholar 

  50. Firestone, R. A., Schelechow, N., Johnston, D. B., Christensen, B. G. (1972) Tetrahedron Letts. 375–378.

  51. Virudachalan, R., Rao, V. R. S. (1977) Int. J. Pept. Protein. Res. 10, 51–59.

    Google Scholar 

  52. Cohen, N. C. (1983) J. Med. Chem. 26, 259–264.

    Google Scholar 

  53. Abraham, E. P., Chain, E. B. (1940) Nature 146, 837.

    Google Scholar 

  54. Inouye, M., ed. (1979) Bacterial Outer Membranes: Biosynthesis and Functions, John Wiley and Sons, N. Y.

    Google Scholar 

  55. Noguchi, H., Matsuhashi, M., Nikaido, T., Itoh, J., Matsubara, N., Takaoka, M., Mitsuhashi, S. (1979) Microb. Drug Resis. 2, 361–387.

    Google Scholar 

  56. Nakae, T., Nikaido, H. (1975) J. Biol. Chem. 250, 7359–7365.

    Google Scholar 

  57. Nakae, T. (1976) J. Biol. Chem. 251, 2176–2178.

    Google Scholar 

  58. Nakae, T. (1976) Biochem. Biophys. Res. Comm. 71, 877–884.

    Google Scholar 

  59. Schindler, H., Rosenbusch, J. P. (1981) Proc. Natl. Acad. Sci. 78, 2302–2306.

    Google Scholar 

  60. Zimmerman, W., Rosselet, A. (1977) Antimicrob. Agents Chemother. 12, 368–372.

    Google Scholar 

  61. Nikaido, H., Rosenberg, E. Y., Foulds, J. (1983) J. Bacteriol. 153, 232–240.

    Google Scholar 

  62. Hamilton-Miller, J. M. T., Smith, J. T., eds, (1979) Beta-Lactamases, Academic Press, London.

    Google Scholar 

  63. Sykes, R. B., Matthew, M. (1976) J. Antimicrob. Chemother. 2, 115–157.

    Google Scholar 

  64. Hamilton-Miller, J. M. T. (1982) J. Antimicrob. Chemother. 9, Supplement B, 11–19.

    Google Scholar 

  65. Matthew, M., Harris, A. M. (1976) J. Gen. Microb. 94, 55–67.

    Google Scholar 

  66. Richmond, M. H., Sykes, R. B. (1973) Adv. Microb. Physiol. 9, 31–88.

    Google Scholar 

  67. Fisher, J., Belasco, J. G., Khosla, S., Knowles, J. R. (1980) Biochemistry 19, 2895–2901.

    Google Scholar 

  68. Knott-Hunziker, V., Redhead, K., Petursson, S., Waley, S. G. (1980) FEBS Letts. 121, 8–10.

    Google Scholar 

  69. Anderson, E. G., Pratt R. F. (1981) J. Biol. Chem. 256, 1401–1404.

    Google Scholar 

  70. Richmond, M. H. (1981) J. Antimicrob. Chemother. 7, 279–285.

    Google Scholar 

  71. Bush, K., Sykes, R. B. (1983) J. Antimicrob. Chemother. 11, 97–107.

    Google Scholar 

  72. O'Callaghan, C. H. (1980) Phil. Trans. R. Soc. Lond. Ser. B. 289, 197–205.

    Google Scholar 

  73. Cole, M. (1980) Phil. Trans. R. Soc. Lond. Ser. B. 289, 207–223.

    Google Scholar 

  74. Fisher, J., Charnas, R. L., Knowles, J. R. (1978) Biochemistry 17, 2180–2184.

    Google Scholar 

  75. Charnas, R. L., Fisher, J., Knowles, J. R. (1978) Biochemistry 17, 2185–2189.

    Google Scholar 

  76. Charnas, R. L., Knowles, J. R. (1981) Biochemistry 20, 3214–3219.

    Google Scholar 

  77. Reading, C., Cole, M. (1977) Antimicrob. Agents Chemother. 11, 852–857.

    Google Scholar 

  78. Pratt, R. F., Loosemore, M. J. (1978) Proc. Nat. Acad. Sci. USA 75, 4145–4149.

    Google Scholar 

  79. Knott-Hunziker, V., Orlek, B. S., Sammes, P. G., Waley, S. G. (1979) Biochem. J. 177, 365–367.

    Google Scholar 

  80. English, A. R., Retsema, J. A., Girard, A. E., Lynch, J. E., Barth, W. E. (1978) Antimicrob. Agents Chemother. 14, 414–419.

    Google Scholar 

  81. Fisher, J., Charnas, R. L., Bradley, S. M., Knowles, J. R. (1981) Biochemistry 20, 2726–2731.

    Google Scholar 

  82. Fisher, J., Belasco, J. G., Charnas, R. L., Khosla, S., Knowles, J. R. (1980) Phil. Trans. R. Soc. Lond. Ser. B. 289, 309–319.

    Google Scholar 

  83. Abeles, R. H., Maycock, A. L. (1976) Acc. Chem. Res. 9, 313–319.

    Google Scholar 

  84. Walsh, C. (1982) Tetrahedron 38, 871–901.

    Google Scholar 

  85. Cartwright, S. J., Coulson, A. F. W. (1979) Nature 278, 360–361.

    Google Scholar 

  86. Mezes, P. S. F., Clarke, A. J., Dmitrienko, G. I., Viswanatha, T. (1982) FEBS Letts. 143, 265–267.

    Google Scholar 

  87. Gottstein, W. J., Crast, L. B., Graham, R. G., Hayes, U. J., McGregor, D. M. (1981) J. Med. Chem. 24, 1531–1534.

    Google Scholar 

  88. Arisawa, M., Then, R. L. (1982) J. Antibiotics 35, 1578–1583.

    Google Scholar 

  89. Arisawa, M., Then, R. L. (1983) Biochem. J. 209, 609–615.

    Google Scholar 

  90. Arisawa, M., Adam, S. (1983) Biochem. J. 211, 447–454.

    Google Scholar 

  91. Charnas, R. L., Knowles, J. R. (1981) Biochemistry 20, 2732–2737.

    Google Scholar 

  92. Easton, C. J., Knowles, J. R. (1982) Biochemistry 21, 2857–2862.

    Google Scholar 

  93. Ambler, R. P. (1980) Phil. Trans. R. Soc. Lond. Ser. B. 289, 321–331.

    Google Scholar 

  94. Jaurin, B., Grundstrom, T. (1981) Proc. Nat. Acad. Sci. USA 78, 4897–4901.

    Google Scholar 

  95. Knott-Hunziker, V., Petursson, S., Waley, S. G., Jaurin, B., Grundstrom, T. (1982) Biochem. J. 207, 315–322.

    Google Scholar 

  96. Leigh, D. A., Robinson, O. P. W., eds. (1982), Augmentin, Excerpta Medica, Amsterdam.

    Google Scholar 

  97. Baltzer, B., Binderup, E., Vandaehn, W., Godtfried, W. O., Hansen, K., Nielson, B., Sorensen, H., Vangedal, S. (1980) J. Antibiotics 33, 1183–1192.

    Google Scholar 

  98. Wise, R. (1981) J. Antimicrob. Chemother. 7, 503–504.

    Google Scholar 

  99. Hartley, S., Wise, R. (1982) J. Antimicrob. Chemother. 10, 49–55.

    Google Scholar 

  100. Christensen, B. G. (1984), in Recent Advances in the Chemistry of Beta-Lactam Antibiotics (Brown, A. G., Roberts, S. M., eds.), The Royal Society of Chemistry, Special Publication, London (in press).

    Google Scholar 

  101. Woodward, R. B. (1976) in Recent Advances in the Chemistry of Beta-Lactam Antibiotics (Elks, J., ed.) pp 167–180, The Chemical Society, Special Publication No 28, London.

    Google Scholar 

  102. Ernest, I. (1982) Reference 2, Vol. 2. pp 315–360.

  103. Mitsuhashi, S., Inoue, M., Saino, Y., Ogashiwa, M. (1982) J. Antimicrob. Chemother. 9, Supplement C, 91–95.

    CAS  PubMed  Google Scholar 

  104. Ganguly, A. K., Girijavallabhan, J. M., McCombie, S., Pinto, P., Rizvi, R., Jeffrey, P. D., Lin, S. (1982). J. Antimicrob. Chemother. 9, Supplement C, 1–5.

    Google Scholar 

  105. Kayser, F. H., Kuhn, I. (1982) J. Antimicrob. Chemother. 9, Supplement C, 181–188.

    Google Scholar 

  106. Ponsford, R. J. (1984) in Recent Advances in the Chemistry of Beta-Lactam Antibiotics (Brown, A. G., Roberts, S. M., eds.), The Royal Society of Chemistry, Special Publication, London (in press).

    Google Scholar 

  107. Knox, J. R. (1984) in Recent Advances in the Chemistry Beta-Lactam Antibiotics (Brown, A. G., Roberts, S. M., eds.), The Royal Society of Chemistry, Special Publication, London (in press).

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacy, University of Nottingham, UK

    Barrie W. Bycroft

Authors
  1. Barrie W. Bycroft
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Richard E. Shute
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bycroft, B.W., Shute, R.E. The Molecular Basis for the Mode of Action of Beta-Lactam Antibiotics and Mechanisms of Resistance. Pharm Res 2, 3–14 (1985). https://doi.org/10.1023/A:1016305704057

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1016305704057

Keywords

Search

Navigation