Skip to main content
SpringerLink
Log in

Lipid II as a Target for Novel Antibiotics: Structural and Molecular Dynamics Studies

  • Review Article
  • Published:
Russian Journal of Bioorganic Chemistry Aims and scope Submit manuscript

Abstract

The growing problem of antibiotic resistance in medicine is focusing attention on antimicrobial compounds targeting non-protein molecules, which have more conserved structures compared to proteins or peptides. One of the most promising and studied targets is lipid II—the bacterial cell wall biosynthetic pathway principal compound. Lipid II is unique for the bacterial membrane only and has a conserved chemical structure. There are several classes of natural antibiotics targeting lipid II, some of which block peptidoglycan synthesis by formation of a strong complex with lipid II; others have an additional bactericidal mechanism involving disruption of the membrane integrity. This review examines the prospects of using such antibacterial substances as new drugs to combat antibiotic-resistant pathogens. The main emphasis is on the studies of the membrane-embedded lipid II structure and how water-soluble antibiotics recognize its molecular structure, as well as on computer modeling of their interaction.

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

Abbreviations

AMP:

antimicrobial peptide

MHP:

molecular hydrophobic potential

MD:

molecular dynamics

CPK:

Corey-Pauling-Koltun model

References

  1. Ventola, C.L., P T, vol. 40, pp. 277–283.

  2. Villa T.G. and Viñas, M., New Weapons to Control Bacterial Growth, Springer Int. Pub., 2016, pp. 1–13.

    Book  Google Scholar 

  3. Arias, C.A. and Murray, B.E., N. Engl. J. Med., 2015, vol. 372, pp. 1168–1170.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Schneider, T. and Sahl, H.-G., Int. J. Med. Microbiol., 2010, vol. 300, pp. 161–169.

    Article  CAS  PubMed  Google Scholar 

  5. Scheffers, D.-J. and Tol, M.B., PLoS Pathog., 2015, vol. 11. e1005213.

    Google Scholar 

  6. Ng, V. and Chan, W.C., Chemistry, 2016, vol. 22, pp. 12606–12616.

    Article  CAS  PubMed  Google Scholar 

  7. Kramer, N.E., Smid, E.J., Kok, J., de Kruijff, B., Kuipers, O.P., and Breukink, E., FEMS Microbiol. Lett., 2004, vol. 239, pp. 157–161.

    Article  CAS  PubMed  Google Scholar 

  8. Brown, E.D., Vivas, E.I., Walsh, C.T., and Kolter, R., J. Bacteriol., 1995, vol. 177, pp. 4194–4197.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Mengin-Lecreulx, D., Flouret, B., and van Heijenoort, J., J. Bacteriol., 1982, vol. 151, pp. 1109–1117.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Bouhss, A., Trunkfield, A.E., Bugg, T.D.H., and Mengin-Lecreulx, D., FEMS Microbiol. Rev., 2008, vol. 32, pp. 208–233.

    Article  CAS  PubMed  Google Scholar 

  11. Mengin-Lecreulx, D., Texier, L., Rousseau, M., and van Heijenoort, J., J. Bacteriol., 1991, vol. 173, pp. 4625–4636.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Typas, A., Banzhaf, M., Gross, C.A., and Vollmer, W., Nat. Rev. Microbiol., 2011, vol. 10, pp. 123–136.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Tatar, L.D., Marolda, C.L., Polischuk, A.N., van Leeuwen, D., and Valvano, M.A., Microbiology, 2007, vol. 153, pp. 2518–2529.

    Article  CAS  PubMed  Google Scholar 

  14. Esko, J.D., Doering, T.L., and Raetz, C.R.H., Essentials of Glycobiology, New York: Cold Spring Harbor Laboratory Press, 2009, chapter 20.

    Google Scholar 

  15. van Heijenoort, J., Microbiol. Mol. Biol. Rev., 2007, vol. 71, pp. 620–635.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Fuchs-Cleveland, E. and Gilvarg, C., Proc. Natl. Acad. Sci. U. S. A., 1976, vol. 73, pp. 4200–4204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Labischinski, H., Goodell, E.W., Goodell, A., and Hochberg, M.L.D., J. Bacteriol., 1991, vol. 173, pp. 751–756.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. van Heijenoort, Y., Gomez, M., Derrien, M., Ayala, J., and van Heijenoort, J., J. Bacteriol., 1992, vol. 174, pp. 3549–3557.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Vollmer, J., Schiefer, A., Schneider, T., Julicher, K., Johnston, K.L., Taylor, M.J., Sahl, H.G., Hoerauf, A., and Pfarr, K.M., Int. J. Med. Microbiol., 2013, vol. 303, pp. 140–149.

    Article  CAS  PubMed  Google Scholar 

  20. Schneider, T. and Sahl, H.-G., Curr. Opin. Investig. Drugs, vol. 11, pp. 157–164.

  21. Zasloff, M., Nature, 2002, vol. 415, pp. 389–395.

    Article  CAS  PubMed  Google Scholar 

  22. Polyansky, A.A., Chugunov, A.O., Vassilevski, A.A., Grishin, E.V., and Efremov, R.G., Curr. Protein Pept. Sci., 2012, vol. 13, pp. 644–657.

    Article  CAS  PubMed  Google Scholar 

  23. Andersson, D.I., Hughes, D., and Kubicek-Sutherland, J.Z., Drug Resist. Updat., 2016, vol. 26, pp. 43–57.

    Article  CAS  PubMed  Google Scholar 

  24. Lee, T.-H., Hall, K.N., and Aguilar, M.-I., Curr. Top. Med. Chem., 2016, vol. 16, pp. 25–39.

    Article  CAS  PubMed  Google Scholar 

  25. Matsuzaki, K., Biochim. Biophys. Acta, 1999, vol. 1462, pp. 1–10.

    Article  CAS  PubMed  Google Scholar 

  26. Yang, L., Weiss, T.M., Lehrer, R.I., and Huang, H.W., Biophys. J., 2000, vol. 79, pp. 2002–2009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Shai, Y., Biochim. Biophys. Acta, 1999, vol. 1462, pp. 55–70.

    Article  CAS  PubMed  Google Scholar 

  28. Le, C.-F., Fang, C.-M., and Sekaran, S.D., Antimicrob. Agents Chemother., 2017, vol. 61. e02340-16.

    Google Scholar 

  29. Arnusch, C.J., Pieters, R.J., and Breukink, E., PLoS One, 2012, vol. 7. e39768.

    Google Scholar 

  30. Barna, J.C. and Williams, D.H., Annu. Rev. Microbiol., 1984, vol. 38, pp. 339–357.

    Article  CAS  PubMed  Google Scholar 

  31. Reynolds, P.E., Eur. J. Clin. Microbiol. Infect. Dis., 1989, vol. 8, no. is. 1989, pp. 943–950.

    Google Scholar 

  32. Wright, G., Nature, 2015, vol. 517, pp. 442–444.

    Article  CAS  PubMed  Google Scholar 

  33. Marshall, C.G., Lessard, I.A., Park, I., and Wright, G.D., Antimicrob. Agents Chemother., 1998, vol. 42, pp. 2215–2220.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Levine, D.P., Clin. Infect. Dis., 2006, vol. 42, no. Suppl. 1, pp. 5–12.

    Google Scholar 

  35. Reynolds, P.E. and Courvalin, P., Antimicrob. Agents Chemother., 2005, vol. 49, pp. 21–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Faron, M.L., Ledeboer, N.A., and Buchan, B.W., J. Clin. Microbiol., 2016, vol. 54, pp. 2436–2447.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Reynolds, P.E., Depardieu, F., Dutka-Malen, S., Arthur, M., and Courvalin, P., Mol. Microbiol., 1994, vol. 13, pp. 1065–1070.

    Article  CAS  PubMed  Google Scholar 

  38. Grohs, P., Gutmann, L., Legrand, R., Schoot, B., and Mainardi, J.L., J. Bacteriol., 2000, vol. 182, pp. 6228–6232.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Hsu, S.-T., Breukink, E., Bierbaum, G., Sahl, H.G., De Kruijff, B., Kaptein, R., Van Nuland, N., and Bonvin, A., J. Biol. Chem., 2003, vol. 278, pp. 13110–13117.

    Article  CAS  PubMed  Google Scholar 

  40. Munch, D. and Sahl, H.-G., Biochim. Biophys. Acta, 2015, vol. 1848, pp. 3062–3071.

    Article  CAS  PubMed  Google Scholar 

  41. Antcheva, N., Guida, F., and Tossi, A., Handbook of Biologically Active Peptides, Elsevier, 2013, pp. 101–118.

    Google Scholar 

  42. Mygind, P.H., Fischer, R.L., Schnorr, K.M., Hansen, M.T., Sonksen, C.P., Ludvigsen, S., Raventos, D., Buskov, S., Christensen, B., De Maria, L., Taboureau, O., Yaver, D., Elvig-Jorgensen, S.G., Sorensen, M.V., Christensen, B.E., Kjaerulff, S., Frimodt-Moller, N., Lehrer, R.I., Zasloff, M., and Kristensen, H.H., Nature, 2005, vol. 437, pp. 975–980.

    Article  CAS  PubMed  Google Scholar 

  43. Schneider, T., Kruse, T., Wimmer, R., Wiedemann, I., Sass, V., Pag, U., Jansen, A., Nielsen, A.K., Mygind, P.H., Raventos, D.S., Neve, S., Ravn, B., Bonvin, A.M., De Maria, L., Andersen, A.S., Gammelgaard, L.K., Sahl, H.G., and Kristensen, H.H., Science, 2010, vol. 328, pp. 1168–1172.

    Article  CAS  PubMed  Google Scholar 

  44. Sass, V., Schneider, T., Wilmes, M., Korner, C., Tossi, A., Novikova, N., Shamova, O., and Sahl, H.G., Infect. Immun., 2010, vol. 78, pp. 2793–2800.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Schmitt, P., Wilmes, M., Pugniere, M., Aumelas, A., Bachere, E., Sahl, H.G., Schneider, T., and Destoumieux-Garzon, D., J. Biol. Chem., 2010, vol. 285, pp. 29208–29216.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Willey, J.M. and van der Donk, W.A., Annu. Rev. Microbiol., 2007, vol. 61, pp. 477–501.

    Article  CAS  PubMed  Google Scholar 

  47. Al-Mahrous, M.M. and Upton, M., Expert Opin. Drug Discov., 2011, vol. 6, pp. 155–170.

    Article  CAS  PubMed  Google Scholar 

  48. Islam, M.R., Nagao, J.-I., Zendo, T., and Sonomoto, K., Biochem. Soc. Trans., 2012, vol. 40, pp. 1528–1533.

    Article  CAS  PubMed  Google Scholar 

  49. Müller, A., Klöckner, A., and Schneider, T., Nat. Prod. Rep., 2017, vol. 34, pp. 909–932.

    Article  PubMed  Google Scholar 

  50. Breukink, E., van Kraaij, C., Demel, R.A., Siezen, R.J., Kuipers, O.P., and de Kruijff, B., Biochemistry, 1997, vol. 36, pp. 6968–6976.

    Article  CAS  PubMed  Google Scholar 

  51. van Kraaij, C., Breukink, E., Noordermeer, M.A., Demel, R.A., Siezen, R.J., Kuipers, O.P., and de Kruijff, B., Biochemistry, 1998, vol. 37, pp. 16033–16040.

    Article  PubMed  Google Scholar 

  52. Bottiger, T., Schneider, T., Martinez, B., Sahl, H.-G., and Wiedemann, I., Appl. Environ. Microbiol., 2009, vol. 75, pp. 4427–4434.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Bionda, N., Pitteloud, J.-P., and Cudic, P., Future Med. Chem., 2013, vol. 5, pp. 1311–1330.

    Article  CAS  PubMed  Google Scholar 

  54. Bassères, E., Endres, B.T., Dotson, K.M., Alam, M.J., and Garey, K.W., Curr. Opin. Gastroenterol., 2017, vol. 33, pp. 1–7.

    Article  CAS  PubMed  Google Scholar 

  55. Han, J., Chen, J., Shao, L., Zhang, J., Dong, X., Liu, P., and Chen, D., PLoS One, 2016, vol. 11. e0154121.

    Google Scholar 

  56. Schneider, T., Muller, A., Miess, H., and Gross, H., Int. J. Med. Microbiol., 2014, vol. 304, pp. 37–43.

    Article  CAS  PubMed  Google Scholar 

  57. Reynolds, P.E. and Somner, E.A., Drugs Exp. Clin. Res., 1990, vol. 16, pp. 385–389.

    CAS  PubMed  Google Scholar 

  58. Fang, X., Tiyanont, K., Zhang, Y., Wanner, J., Boger, D., and Walker, S., Mol. Biosyst., 2006, vol. 2, pp. 69–76.

    Article  CAS  PubMed  Google Scholar 

  59. Lo, M.-C., Men, H., Branstrom, A., Helm, J., Yao, N., Goldman, R., and Walke, S., J. Am. Chem. Soc., 2000, vol. 122, pp. 3540–3541.

    Article  CAS  Google Scholar 

  60. Cheng, M., Huang, J.X., Ramu, S., Butler, M.S., and Cooper, M.A., Antimicrob. Agents Chemother., vol. 58, pp. 6819–6827.

  61. Hu, Y., Helm, J.S., Chen, L., Ye, X.-Y., and Walker, S., J. Am. Chem. Soc., 2003, vol. 125, pp. 8736–8737.

    Article  CAS  PubMed  Google Scholar 

  62. Ling, L.L., Schneider, T., Peoples, A.J., Spoering, A.L., Engels, I., Conlon, B.P., Mueller, A., Schäberle, T.F., Hughes, D.E., Epstein, S., Jones, M., Lazarides, L., Steadman, V.A., Cohen, D.R., Felix, C.R., Fetterman, K.A., Millett, W.P., Nitti, A.G., Zullo, A.M., Chen, C., and Lewis, K., Nature, 2015, vol. 517, pp. 455–459.

    Article  CAS  PubMed  Google Scholar 

  63. Piggot, T.J., Holdbrook, D.A., and Khalid, S., J. Phys. Chem. B, vol. 115, pp. 13381–13388.

  64. Chugunov, A., Pyrkova, D., Nolde, D., Polyansky, A., Pentkovsky, V., and Efremov, R., Sci. Rep., 2013, vol. 3, p. 1678.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Panina, I.S., Nol’de, D.E., Chugunov, A.O., and Efremov, R.G., Akt. Vopr. Biol. Fiz. Khim., 2016, vol. 1, pp. 263–267.

    Google Scholar 

  66. de Kruijff, B., van Dam, V., and Breukink, E., Prostaglandins Leukot. Essent. Fatty Acids, 2008, vol. 79, pp. 117–121.

    Article  CAS  PubMed  Google Scholar 

  67. Hasper, H.E., Kramer, N.E., Smith, J.L., Hillman, J.D., Zachariah, C., Kuipers, O.P., de Kruijff, B., and Breukink, E., Science, 2016, vol. 313, pp. 1636–1637.

    Article  CAS  Google Scholar 

  68. Hasper, H.E., de Kruijff, B., and Breukink, E., Biochemistry, 2004, vol. 43, pp. 11567–11575.

    Article  CAS  PubMed  Google Scholar 

  69. Witzke, S., Petersen, M., Carpenter, T.S., and Khalid, S., Biochemistry, 2016, vol. 55, pp. 3303–3314.

    Article  CAS  PubMed  Google Scholar 

  70. Prossnigg, F., Hickel, A., Pabst, G., and Lohner, K., Biophys. Chem., 2010, vol. 150, pp. 129–135.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Sosa, MoralesM.C. and Alvarez, R.M.S., J. Raman Spectrosc., 2017, vol. 48, pp. 170–179.

    Article  CAS  Google Scholar 

  72. Hsu, S.-T.D., Breukink, E., Tischenko, E., Lutters, M.A., de Kruijff, B., Kaptein, R., Bonvin, A.M., and van Nuland, N.A., Nat. Struct. Mol. Biol., 2004, vol. 11, pp. 963–967.

    Article  CAS  PubMed  Google Scholar 

  73. Oppedijk, S.F., Martin, N.I., and Breukink, E., Biochim. Biophys. Acta, 2016, vol. 1858, pp. 947–957.

    Article  CAS  PubMed  Google Scholar 

  74. Szekat, C., Jack, R.W., Skutlarek, D., Farber, H., and Bierbaum, G., Appl. Environ. Microbiol., 2003, vol. 69, pp. 3777–3783.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Brotz, H., Bierbaum, G., Leopold, K., Reynolds, P.E., and Sahl, H.G., Antimicrob. Agents Chemother., 1998, vol. 42, pp. 154–160.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Yang, H., Du Bois D.R., Ziller, J.W., and Nowick, J.S., Chem. Commun., 2017, vol. 53, pp. 2772–2775.

    Article  CAS  Google Scholar 

  77. Parmar, A., Iyer, A., Vincent, C.S., Van Lysebetten, D., Prior, S.H., Madder, A., Taylor, E.J., and Singh, I., Chem. Commun., 2016, vol. 52, pp. 6060–6063.

    Article  CAS  Google Scholar 

  78. Yang, H., Chen, K.H., and Nowick, J.S., ACS Chem. Biol., 2016, vol. 11, pp. 1823–1826.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Mulholland, S., Turpin, E.R., Bonev, B.B., and Hirst, J.D., Sci. Rep., 2016, vol. 6, p. 21185.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Prince, A., Sandhu, P., Kumar, P., Dash, E., Sharma, S., Arakha, M., Jha, S., Akhter, Y., and Saleem, M., Sci. Rep., 2016, vol. 6, p. 37908.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Franzoi, M., van Heuvel, Y., Thomann, S., Schurch, N., Kallio, P.T., Venier, P., and Essig, A., Biochemistry, 2017, vol. 56, pp. 4992–5001.

    Article  CAS  PubMed  Google Scholar 

  82. Liu, Y., Liu, Y., Chan-Park, M.B., and Mu, Y., Sci. Rep., 2017, vol. 7, p. 17197.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Lungu, C.N. and Diudea, M.V., Comput. Aided Drug Des., 2018, vol. 14, pp. 29–34.

    Article  CAS  Google Scholar 

  84. Panina, I.S., Nol’de, D.E., Krylov, N.A., and Efremov, R.G., Akt. Vopr. Biol. Fiz. Khim., 2017, vol. 2, pp. 528–532.

    Google Scholar 

  85. Bocharov, E.V., Lesovoy, D.M., Bocharova, O.V., Urban, A.S., Pavlov, K.V., Volynsky, P.E., Efremov, R.G., and Arseniev, A.S., Biochim. Biophys. Acta, 2018, vol. 1862, pp. 1410–1420.

    Article  CAS  Google Scholar 

  86. Kuznetsov, A.S., Polyansky, A.A., Fleck, M., Volynsky, P.E., and Efremov, R.G., J. Chem. Theory Comput., 2015, vol. 11, pp. 4415–4426.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, 119779, Russia

    I. S. Panina, A. O. Chugunov & R. G. Efremov

  2. National Research University Higher School of Economics, Moscow, 101000, Russia

    A. O. Chugunov & R. G. Efremov

Authors
  1. I. S. Panina
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. O. Chugunov
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R. G. Efremov
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to I. S. Panina.

Additional information

The paper is published based on the material of a report presented at the “Lipids of the XXI Century. The First Quarter” conference, October 22–23, 2018, Moscow.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Panina, I.S., Chugunov, A.O. & Efremov, R.G. Lipid II as a Target for Novel Antibiotics: Structural and Molecular Dynamics Studies. Russ J Bioorg Chem 44, 653–664 (2018). https://doi.org/10.1134/S1068162019010126

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S1068162019010126

Keywords

Search

Navigation