Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Lipid II as a target for antibiotics

Nature Reviews Drug Discovery volume 5, pages 321–323 (2006)Cite this article

Key Points

  • The bacterial membrane-anchored cell-wall precursor Lipid II can be considered an Achilles' heel of bacteria, as it is an essential component of bacterial cell walls and is a relatively easily accessible target for antibiotics.

  • Lipid II is targeted by at least four classes of antibiotic: glycopeptides (for example, vancomycin); lantibiotics (for example, nisin); ramoplanin; and mannopeptimycins.

  • There is no antibiotic in clinical use today to which resistance has not developed, including vancomycin. This has led to increasing interest in the therapeutic potential of other classes of compound that target Lipid II, including ramoplanin and the mannopeptimycins.

  • The lantibiotic nisin binds to the pyrophosphate moiety of Lipid II, and this binding is thought to involve the formation of at least five hydrogen bonds between backbone amine functionalities of nisin and oxygen atoms of the phosphate groups of Lipid II. It is known that amino acids in the D-configuration are essential for this binding interaction.

  • The mechanism of action of ramoplanin and the mannopeptimycins has yet to be elucidated, but it is thought that the unusual amino acids, such as D-amino acids and glycosylated amino acids, in the peptide backbones of these and other antibiotics that target Lipid II are important in the binding of these antibiotics to Lipid II.

  • The Lipid-II-targeting antibiotics have a broad spectrum of activity: they are suitably active against most, if not all, Gram-positive bacteria and the lantibiotic nisin also has potent activity against some Gram-negative bacteria.

  • Resistance of bacteria to nisin is generally achieved by a shielding mechanism in which incorporation of positive charges in the cell wall repels nisin from the bacterial cells, thereby preventing it from reaching Lipid II. However, resistance to ramoplanin or mannopeptimycins has not yet been reported.

  • In vitro screening has shown that all the tested lantibiotics show promising activity against multi-resistant and vancomycin-resistant strains. Lipid II production is restricted to bacteria, and so these antibiotics should have low toxicity in humans. This highlights their potential as new clinical antibiotics for the treatment of resistant infections.

Abstract

Lipid II is a membrane-anchored cell-wall precursor that is essential for bacterial cell-wall biosynthesis. The effectiveness of targeting Lipid II as an antibacterial strategy is highlighted by the fact that it is the target for at least four different classes of antibiotic, including the clinically important glycopeptide antibiotic vancomycin. However, the growing problem of bacterial resistance to many current drugs, including vancomycin, has led to increasing interest in the therapeutic potential of other classes of compound that target Lipid II. Here, we review progress in understanding of the antibacterial activities of these compounds, which include lantibiotics, mannopeptimycins and ramoplanin, and consider factors that will be important in exploiting their potential as new treatments for bacterial infections.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Schematic presentation of the cell-wall synthesis cycle.
Figure 2: Structures of antibiotics that target Lipid II.
Figure 3: Post-translational modifications in nisin.
Figure 4: Model for the target-directed pore-formation mechanism of nisin.
Figure 5: Interaction of nisin with Lipid II: the pyrophosphate cage.

Similar content being viewed by others

References

  1. Weigel, L. M. et al. Genetic analysis of a high-level vancomycin-resistant isolate of Staphylococcus aureus. Science 302, 1569–1571 (2003).

    Article  CAS  PubMed  Google Scholar 

  2. Harz, H., Burgdorf, K. & Holtje, J.-V. Isolation and separation of the glycan strands from murein of Escherichia coli by reversed-phase high-performance liquid chromatography. Anal. Biochem. 190, 120–128 (1990).

    Article  CAS  PubMed  Google Scholar 

  3. Kramer, N. E. et al. Resistance of Gram-positive bacteria to nisin is not determined by Lipid II levels. FEMS Microbiol. Lett. 239, 157–161 (2004).

    Article  CAS  PubMed  Google Scholar 

  4. Stone, K. J. & Strominger, J. L. Binding of bacitracin to cells and protoplasts of Micrococcus lysodeikticus. J. Biol. Chem. 249, 1823–1827 (1973).

    Google Scholar 

  5. Labischinski, H., Goodell, E. W., Goodell, A. & Hochberg, M. L. Direct proof of a 'more than single-layered' peptidoglycan architecture of Escherichia coli. J. Bacteriol. 136, 723–729 (1991).

    Google Scholar 

  6. McCloskey, M. A. & Troy, F. A. Paramagnetic isoprenoid carrier lipids. 2. Dispersion and dynamics in lipid membranes. Biochemistry 19, 2061–2066 (1980).

    Article  CAS  PubMed  Google Scholar 

  7. Chatterjee, C., Paul, M., Xie, L. L. & van der Donk, W. A. Biosynthesis and mode of action of lantibiotics. Chem. Rev. 105, 633–683 (2005). An in-depth review of aspects of the synthesis and mode of action of lantibiotics.

    Article  CAS  PubMed  Google Scholar 

  8. Ekkelenkamp, M. B. et al. Isolation and structural characterization of epilancin 15X, a novel lantibiotic from a clinical strain of Staphylococcus epidermidis. FEBS Lett. 579, 1917–1922 (2005).

    Article  CAS  PubMed  Google Scholar 

  9. Rogers, L. A. The inhibiting effect of Streptococcus lactis on Lactobacillus bulgaricus. J. Bacteriol. 16, 321–325 (1928).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Rogers, L. A. & Whittier, E. O. Limiting factors in the lactic fermentation. J. Bacteriol. 16, 211–229 (1928).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Delves-Broughton, J., Blackburn, P., Evans, R. J. & Hugenholtz, J. Applications of the bacteriocin, nisin. Antonie Van Leeuwenhoek 69, 193–202 (1996).

    Article  CAS  PubMed  Google Scholar 

  12. Linnett, P. E. & Strominger, J. L. Additional antibiotic inhibitors of peptidoglycan synthesis. J. Biol. Chem. 4, 231–236 (1973). First article describing the binding of nisin to Lipid II.

    CAS  Google Scholar 

  13. Reisinger, P., Seidel, H., Tschesche, H. & Hammes, W. P. The effect of nisin on murein synthesis. Arch. Microbiol. 127, 187–193 (1980).

    Article  CAS  PubMed  Google Scholar 

  14. Sahl, H.-G. in Nisin and Novel Lantibiotics (eds. Jung, G. & Sahl, H.-G.) 347–358 (ESCOM Science, Leiden, 1991).

    Google Scholar 

  15. Ruhr, E. & Sahl, H. G. Mode of action of the peptide antibiotic nisin and influence on the membrane potential of whole cells and on cytoplasmic and artificial membrane vesicles. Antimicrob. Agents Chemother. 27, 841–845 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Garcera, M. J., Elferink, M. G., Driessen, A. J. & Konings, W. N. In vitro pore-forming activity of the lantibiotic nisin. Role of protonmotive force and lipid composition. Eur. J. Biochem. 212, 417–422 (1993).

    Article  CAS  PubMed  Google Scholar 

  17. Breukink, E. et al. The C-terminal region of nisin is responsible for the initial interaction of nisin with the target membrane. Biochemistry 36, 6968–6976 (1997).

    Article  CAS  PubMed  Google Scholar 

  18. Breukink, E., Ganz, P., de Kruijff, B. & Seelig, J. Binding of nisin Z to bilayer vesicles as determined with isothermal titration calorimetry. Biochemistry 39, 10247–10254 (2000).

    Article  CAS  PubMed  Google Scholar 

  19. Martin, I., Ruysschaert, J. M., Sanders, D. & Giffard, C. J. Interaction of the lantibiotic nisin with membranes revealed by fluorescence quenching of an introduced tryptophan. Eur. J. Biochem. 239, 156–164 (1996).

    Article  CAS  PubMed  Google Scholar 

  20. Brotz, H. et al. Role of lipid-bound peptidoglycan precursors in the formation of pores by nisin, epidermin and other lantibiotics. Mol. Microbiol. 30, 317–327 (1998).

    Article  CAS  PubMed  Google Scholar 

  21. Breukink, E. et al. Use of the cell wall precursor lipid II by a pore-forming peptide antibiotic. Science 286, 2361–2364 (1999). The authors describe how nisin exploits Lipid II in pore formation.

    Article  CAS  PubMed  Google Scholar 

  22. Matsuzaki, K., Murase, O., Fujii, N. & Miyajima, K. Translocation of a channel-forming antimicrobial peptide, magainin 2, across lipid bilayers by forming a pore. Biochemistry 34, 6521–6526 (1995).

    Article  CAS  PubMed  Google Scholar 

  23. van Kraaij, C. et al. Pore formation by nisin involves translocation of its C-terminal part across the membrane. Biochemistry 37, 16033–16040 (1998).

    Article  CAS  PubMed  Google Scholar 

  24. Brogden, K. A. Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria? Nature Rev. Microbiol. 3, 238–250 (2005).

    Article  CAS  Google Scholar 

  25. Wiedemann, I. et al. Specific binding of nisin to the peptidoglycan precursor lipid II combines pore formation and inhibition of cell wall biosynthesis for potent antibiotic activity. J. Biol. Chem. 276, 1772–1779 (2001).

    Article  CAS  PubMed  Google Scholar 

  26. Breukink, E. et al. The orientation of nisin in membranes. Biochemistry 37, 8153–8162 (1998).

    Article  CAS  PubMed  Google Scholar 

  27. Sahl, H. G., Kordel, M. & Benz, R. Voltage-dependent depolarization of bacterial membranes and artificial lipid bilayers by the peptide antibiotic nisin. Arch. Microbiol. 149, 120–124 (1987).

    Article  CAS  PubMed  Google Scholar 

  28. van Heusden, H. E., de Kruijff, B. & Breukink, E. Lipid II induces a transmembrane orientation of the pore forming peptide lantibiotic nisin. Biochemistry 41, 12171–12178 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. Wiedemann, I., Benz, R. & Sahl, H.-G. Lipid II-mediated pore formation by the peptide antibiotic nisin — a black lipid membrane study. J. Bacteriol. 186, 3259–3261 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Breukink, E. et al. Lipid II is an intrinsic component of the pore induced by nisin in bacterial membranes. J. Biol. Chem. 278, 19898–19903 (2003).

    Article  CAS  Google Scholar 

  31. Bonev, B. B., Breukink, E., Swiezewska, E., de Kruijff, B. & Watts, A. Targeting extracellular pyrophosphates underpins the high selectivity of nisin. FASEB J. 18, 1862–1869 (2004).

    Article  CAS  PubMed  Google Scholar 

  32. Hasper, H. E., de Kruijff, B. & Breukink, E. Assembly and stability of nisin–Lipid II pores. Biochemistry 43, 11567–11575 (2004).

    Article  CAS  PubMed  Google Scholar 

  33. Hsu, S. T. D. et al. The nisin–lipid II complex reveals a pyrophosphate cage that provides a blueprint for novel antibiotics. Nature Struct. Mol. Biol. 11, 963–967 (2004).

    Article  CAS  Google Scholar 

  34. Chan, W. C. et al. Structure–activity relationships in the peptide antibiotic nisin: antibacterial activity of fragments of nisin. FEBS Lett. 390, 129–132 (1996).

    Article  CAS  PubMed  Google Scholar 

  35. Arthur, M. & Courvalin, P. Genetics and mechanisms of glycopeptide resistance in Enterococci. Antimicrob. Agents Chemother. 37, 1563–1571 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Brotz, H., Bierbaum, G., Leopold, K., Reynolds, P. E. & Sahl, H.-G. The lantibiotic mersacidin inhibits peptidoglycan synthesis by targeting Lipid II. Antimicrob. Agents Chemother. 42, 154–160 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Hsu, S. T. D. et al. NMR study of mersacidin and lipid II interaction in dodecylphosphocholine micelles — conformational changes are a key to antimicrobial activity. J. Biol. Chem. 278, 13110–13117 (2003).

    Article  CAS  PubMed  Google Scholar 

  38. Martin, N. I. et al. Structural characterization of lacticin 3147, a two-peptide lantibiotic with synergistic activity. Biochemistry 43, 3049–3056 (2004).

    Article  CAS  PubMed  Google Scholar 

  39. Cavalleri, B., Pagani, H., Volpe, G., Selva, E. & Parenti, F. A-16686, a new antibiotic from Actinoplanes. I. Fermen-tation, isolation and preliminary physico-chemical characteristics. J. Antibiot. (Tokyo) 37, 309–317 (1984).

    Article  CAS  Google Scholar 

  40. McCafferty, D. G. et al. Chemistry and biology of the ramoplanin family of peptide antibiotics. Biopolymers 66, 261–284 (2002).

    Article  CAS  PubMed  Google Scholar 

  41. Walker, S. et al. Chemistry and biology of ramoplanin: a lipoglycodepsipeptide with potent antibiotic activity. Chem. Rev. 105, 449–476 (2005). An in-depth review that describes aspects of the synthesis and mode of action of ramoplanin.

    Article  CAS  PubMed  Google Scholar 

  42. Cudic, P. et al. Complexation of peptidoglycan intermediates by the lipoglycodepsipeptide antibiotic ramoplanin: minimal structural requirements for intermolecular complexation and fibril formation. Proc. Natl Acad. Sci. USA 99, 7384–7389 (2002).

    Article  CAS  PubMed  Google Scholar 

  43. Rew, Y., Shin, D., Hwang, I. & Boger, D. L. Total synthesis and examination of three key analogues of ramoplanin: a lipoglycodepsipeptide with potent antibiotic activity. J. Am. Chem. Soc. 126, 1041–1043 (2004).

    Article  CAS  PubMed  Google Scholar 

  44. Jiang, W., Wanner, J., Lee, R. J., Bounaud, P. Y. & Boger, D. L. Total synthesis of the ramoplanin A2 and ramoplanose aglycon. J. Am. Chem. Soc. 125, 1877–1887 (2003).

    Article  CAS  PubMed  Google Scholar 

  45. Helm, J. S., Chen, L. & Walker, S. Rethinking ramoplanin: the role of substrate binding in inhibition of peptidoglycan biosynthesis. J. Am. Chem. Soc. 124, 13970–13971 (2002).

    Article  CAS  PubMed  Google Scholar 

  46. Ciabatti, R., Maffioli, S. I., Romano, G., Candiani, G. & Panzone, G. A process for the production of ramoplanin-like amide derivatives. Chem. Abstr. 139, 261566 (2003).

    Google Scholar 

  47. Chen, L. et al. Dissecting ramoplanin: mechanistic analysis of synthetic ramoplanin analogues as a guide to the design of improved antibiotics. J. Am. Chem. Soc. 126, 7462–7463 (2004).

    Article  CAS  PubMed  Google Scholar 

  48. Cudic, P. et al. Functional analysis of the lipoglycodepsipeptide antibiotic ramoplanin. Chem. Biol. 9, 897–906 (2002).

    Article  CAS  PubMed  Google Scholar 

  49. Watson, J. D. & Milner-White, E. J. A novel main-chain anion-binding site in proteins: The nest. A particular combination of phi, psi values in successive residues gives rise to anion-binding sites that occur commonly and are found often at functionally important regions. J. Mol. Biol. 315, 171–182 (2002).

    Article  CAS  PubMed  Google Scholar 

  50. Watson, J. D. & Milner-White, E. J. The conformations of polypeptide chains where the main-chain parts of successive residues are enantiomeric. Their occurrence in cation and anion-binding regions of proteins. J. Mol. Biol. 315, 183–1191 (2002).

    Article  CAS  PubMed  Google Scholar 

  51. Singh, M. P. et al. Mannopeptimycins, new cyclic glycopeptide antibiotics produced by Streptomyces hygroscopicus LL-AC98: antibacterial and mechanistic activities. Antimicrob. Agents Chemother. 47, 62–69 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. He, H. et al. Mannopeptimycins, novel antibacterial glycopeptides from Streptomyces hygroscopicus, LL-AC98. J. Am. Chem. Soc. 124, 9729–9736 (2002).

    Article  CAS  PubMed  Google Scholar 

  53. Dushin, R. G. et al. Hydrophobic acetal and ketal derivatives of mannopeptimycin-a and desmethylhexa-hydromannopeptimycin-a: semisynthetic glycopeptides with potent activity against Gram-positive bacteria. J. Med. Chem. 47, 3487–3490 (2004).

    Article  CAS  PubMed  Google Scholar 

  54. Ruzin, A. et al. Mechanism of action of the mannopeptimycins, a novel class of glycopeptide antibiotics active against vancomycin-resistant Gram-positive bacteria. Antimicrob. Agents Chemother. 48, 728–738 (2004). The authors show that the mannopeptimycins target Lipid II.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Shoji, J. et al. Isolation and characterization of new peptide antibiotics, plusbacins A1-A4 and B1-B4. J. Antibiot. (Tokyo) 45, 817–823 (1992).

    Article  CAS  Google Scholar 

  56. Shoji, J. et al. Isolation and characterization of katanosins A and B. J. Antibiot. (Tokyo) 41, 713–718 (1988).

    Article  CAS  Google Scholar 

  57. Maki, H., Miura, K. & Yamano, Y. Katanosin B and plusbacin A3, inhibitors of peptidoglycan synthesis in methicillin-resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 45, 1823–1827 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Jarvis, B. Resistance to nisin and production of nisin-inactivating enzymes by several Bacillus species. J. Gen. Microbiol. 47, 33–48 (1967).

    Article  CAS  PubMed  Google Scholar 

  59. Jarvis, B. & Farr, J. Partial purification, specificity and mechanism of action of the nisin-inactivating enzyme from Bacillus cereus. Biochim. Biophys. Acta 227, 232–240 (1971).

    Article  CAS  PubMed  Google Scholar 

  60. Froseth, B. R. & McKay, L. L. Molecular characterization of the nisin resistance region of Lactococcus-lactis subsp lactis biovar diacetylactis Drc3. Appl. Environ. Microbiol. 57, 804–811 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Mantovani, H. C. & Russell, J. B. Nisin resistance of Streptococcus bovis. Appl. Environ. Microbiol. 67, 808–813 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Breuer, B. & Radler, F. Inducible resistance against nisin in Lactobacillus casei. Arch. Microbiol. 165, 114–118 (1996).

    Article  CAS  Google Scholar 

  63. Severina, E., Severin, A. & Tomasz, A. Antibacterial efficacy of nisin against multidrug-resistant Gram positive pathogens. J. Antimicrob. Chemother. 41, 341–347 (1998).

    Article  CAS  PubMed  Google Scholar 

  64. MaisnierPatin, S. & Richard, J. Cell wall changes in nisin-resistant variants of Listeria innocua grown in the presence of high nisin concentrations. FEMS Microbiol. Lett. 140, 29–35 (1996).

    Article  CAS  Google Scholar 

  65. Verheul, A., Russell, N. J., van't Hof, R., Rombouts, F. M. & Abee, T. Modifications of membrane phospholipid composition in nisin-resistant Listeria monocytogenes Scott A. Appl. Environ. Microbiol. 63, 3451–3457 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Crandall, A. D. & Montville, T. J. Nisin resistance in Listeria monocytogenes ATCC 700302 is a complex phenotype. Appl. Environ. Microbiol. 64, 231–237 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Davies, E. A., Falahee, M. B. & Adams, M. R. Involvement of the cell envelope of Listeria monocytogenes in the acquisition of nisin resistance. J. Appl. Bacteriol. 81, 139–146 (1996).

    Article  CAS  PubMed  Google Scholar 

  68. Neuhaus, F. C. & Baddiley, J. A continuum of anionic charge: structures and functions of D-Alanyl-Teichoic acids in Gram-positive bacteria. Microb. Mol. Biol. Rev. 67, 686–723 (2003).

    Article  CAS  Google Scholar 

  69. Kramer, N. E. Nisin resistance in Gram-positive bacteria. Ph.D. Thesis, Utrecht Univ. (2005).

  70. Cao, M. & Helmann, J. D. The Bacillus subtilis extracytoplasmic-function sigma(X) factor regulates modification of the cell envelope and resistance to cationic antimicrobial peptides. J. Bacteriol. 186, 1136–1146 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Farver, D. K., Hedge, D. D. & Lee, S. C. Ramoplanin: a lipoglycodepsipeptide antibiotic. Ann. Pharmacother. 39, 863–868 (2005).

    Article  CAS  PubMed  Google Scholar 

  72. Brumfitt, W., Salton, M. R. J. & Hamilton-Miller, J. M. T. Nisin, alone and combined with peptidoglycan-modulating antibiotics: activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. J. Antimicrob. Chemother. 50, 731–734 (2002).

    Article  CAS  PubMed  Google Scholar 

  73. Bavin, E. M., Beach, A. S., Falconer, R. & Friedman, R. Nisin in experimental tuberculosis. The Lancet 259, 127–129 (1952).

    Article  Google Scholar 

  74. Mota-Meira, M., LaPointe, G., Lacroix, C. & Lavoie, M. C. MICs of mutacin B-Ny266, nisin A, vancomycin, and oxacillin against bacterial pathogens. Antimicrob. Agents Chemother. 44, 24–29 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Peschel, A. et al. Inactivation of the dlt operon in Staphylococcus aureus confers sensitivity to defensins, protegrins, and other antimicrobial peptides. J. Biol. Chem. 274, 8405–8410 (1999). Describes how the incorporation of positively charged residues ( D -Ala) in the cell wall affects resistance to peptide antibiotics.

    Article  CAS  PubMed  Google Scholar 

  76. Stevens, K. A., Sheldon, B. W., Klapes, N. A. & Klaenhammer, T. R. Nisin treatment for inactivation of Salmonella species and other Gram-negative bacteria. Appl. Environ. Microbiol. 57, 3613–3615 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Yuan, J., Zhang, Z. Z., Chen, X. Z., Yang, W. & Huan, L. D. Site-directed mutagenesis of the hinge region of nisinZ and properties of nisinZ mutants. Appl. Microbiol. Biotechnol. 64, 806–815 (2004).

    Article  CAS  PubMed  Google Scholar 

  78. He, H. Mannopeptimycins, a novel class of glycopeptide antibiotics active against Gram-positive bacteria. Appl. Microbiol. Biotechnol. 67, 444–452 (2005).

    Article  CAS  PubMed  Google Scholar 

  79. Goldstein, B. P., Wei, J., Greenberg, K. & Novick, R. Activity of nisin against Streptococcus pneumoniae, in vitro, a mouse infection model. J. Antimicrob. Chemother. 42, 277–278 (1998).

    Article  CAS  PubMed  Google Scholar 

  80. Kordel, M. & Sahl, H. G. Susceptibility of bacterial, eukaryotic and artificial membranes to the disruptive action of the cationic peptides Pep 5 and nisin. FEMS Microbiol. Lett. 34, 139–144 (1986).

    Article  CAS  Google Scholar 

  81. Chatterjee, S. et al. Mersacidin, a new antibiotic from Bacillus. In vitro and in vivo antibacterial activity. J. Antibiot. (Tokyo) 45, 839–845 (1992).

    Article  CAS  Google Scholar 

  82. Kruszewska, D. et al. Mersacidin eradicates methicillin-resistant Staphylococcus aureus (MRSA) in a mouse rhinitis model. J. Antimicrob. Chemother. 54, 648–653 (2004).

    Article  CAS  PubMed  Google Scholar 

  83. Weiss, W. J., Murphy, T., Lenoy, E. & Young, M. In vivo efficacy and pharmacokinetics of AC98–6446, a novel cyclic glycopeptide, in experimental infection models. Antimicrob. Agents Chemother. 48, 1708–1712 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. McCormick, M. H., McGuire, J. M., Pittenger, G. E., Pittenger, R. C. & Stark, W. M. Vancomycin, a new antibiotic. I. Chemical and biologic properties. Antibiot. Annu. 3, 606–611 (1956).

    CAS  Google Scholar 

  85. Williamson, M. P. & Williams, D. H. Structure revision of the antibiotic vancomycin. Use of nuclear Overhauser effect difference spectroscopy. J. Am. Chem. Soc. 103, 6580–6585 (1981).

    Article  CAS  Google Scholar 

  86. 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 271, 223–225 (1978). Describes elucidation of the binding interactions formed between vancomycin and Lipid II.

    Article  CAS  PubMed  Google Scholar 

  87. Harris, C. M. & Harris, T. M. Structure of the glycopeptide antibiotic vancomycin. Evidence for an asparagine residue in the peptide. J. Am. Chem. Soc. 104, 4293–4295 (1982).

    Article  CAS  Google Scholar 

  88. Anderson, J. S., Matsuhashi, M., Haskin, M. A. & Strominger, J. L. Lipid-phosphoacetylmuramyl-pentapeptide and lipid-phosphodisaccharide-pentapeptide: presumed membrane transport intermediates in cell wall synthesis. Proc. Natl Acad. Sci. USA 53, 881–889 (1965).

    Article  CAS  PubMed  Google Scholar 

  89. Perkins, H. R. Specificity of combination between mucopeptide precursors and vancomycin or ristocetin. Biochem. J. 111, 195–205 (1969).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Chatterjee, A. N. & Perkins, H. R. Compounds formed between nucleotides related to the biosynthesis of bacterial cell wall and vancomycin. Biochem. Biophys. Res. Commun. 24, 489–494 (1966).

    Article  CAS  PubMed  Google Scholar 

  91. Bordet, C. & Perkins, H. R. Iodinated vancomycin and mucopeptide biosynthesis by cell-free preparations from Micrococcus lysodeikticus. Biochem. J. 119, 877–883 (1970).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Molinari, H., Pastore, A., Lian, L. Y., Hawkes, G. E. & Sales, K. Structure of vancomycin and a vancomycin/D-Ala-D-Ala complex in solution. Biochemistry 29, 2271–2277 (1990).

    Article  CAS  PubMed  Google Scholar 

  93. Vollmerhaus, P. J., Breukink, E. & Heck, A. J. Getting closer to the real bacterial cell wall target: biomolecular interactions of water-soluble lipid II with glycopeptide antibiotics. Chemistry 9, 1556–1565 (2003).

    Article  CAS  PubMed  Google Scholar 

  94. Malabarba, A. & Goldstein, B. P. Origin, structure, and activity in vitro and in vivo of dalbavancin. J. Antimicrob. Chemother. 55 (Suppl. 2), ii15–20 (2005).

    Article  CAS  PubMed  Google Scholar 

  95. Higgins, D. L. et al. Telavancin, a multifunctional lipoglycopeptide, disrupts both cell wall synthesis and cell membrane integrity in methicillin-resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 49, 1127–1134 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Mercier, R. C. & Hrebickova, L. Oritavancin: a new avenue for resistant Gram-positive bacteria. Expert Rev. Anti Infect. Ther. 3, 325–332 (2005).

    Article  CAS  PubMed  Google Scholar 

  97. Barrett, M. S., Wenzel, R. P. & Jones, R. N. In vitro activity of mersacidin (M87-1551), an investigational peptide antibiotic tested against gram-positive bloodstream isolates. Diagn. Microbiol. Infect. Dis. 15, 641–644 (1992).

    Article  CAS  PubMed  Google Scholar 

  98. Petersen, P. J., Wang, T. Z., Dushin, R. G. & Bradford, P. A. Comparative in vitro activities of AC98–6446, a novel semisynthetic glycopeptide derivative of the natural product mannopeptimycin alpha, and other antimicrobial agents against Gram-positive clinical isolates. Antimicrob. Agents Chemother. 48, 739–746 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biochemistry of Membranes, Bijvoet Center for Biomolecular Research, Utrecht University, Padualaan 8, Utrecht, 3584CH, The Netherlands

    Eefjan Breukink & Ben de Kruijff

Authors
  1. Eefjan Breukink
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ben de Kruijff
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eefjan Breukink.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Pfizer dalbavancin approval

Targanta pipeline

Theravance telavancin development

Glossary

Nest–egg principle

The nest–egg principle applies to atoms or molecules with a full or partially negative charge (eggs) that sit in concave depressions ('nests') of a protein structure. The NH groups of the amino acids that form the nest point into the depression such that they can serve as a binding site for the atom or group of atoms.

Isogenic

Bacteria (and other organisms) are isogenic if they are characterized by essentially identical genes.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Breukink, E., de Kruijff, B. Lipid II as a target for antibiotics. Nat Rev Drug Discov 5, 321–323 (2006). https://doi.org/10.1038/nrd2004

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd2004

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing