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  • 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.

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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.

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    Eefjan Breukink & Ben de Kruijff

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Correspondence to Eefjan Breukink.

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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.

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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

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