Lipid II as a target for antibiotics

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.

Through the Looking Glass, Mechanistic Insights from Enantiomeric Human Defensins

“…Because the ability of nisin to induce liposomal leakage markedly increased by several orders of magnitude in the presence of Lipid II, a membrane-bound peptidoglycan precursor, it was suggested that nisin specifically binds to the pyrophosphate moiety of Lipid II for enhanced bacterial membrane permeabilization (75). More recently, nisin has been reported to displace Lipid II from the cell division site to block cell wall synthesis (76), a bacterial killing mechanism reminiscent of vancomycin (77). These findings raise an intriguing possibility, that is, HNP1 and HD5 may use some components of the bacterial cell wall or of the cytoplasmic membrane as docking molecules for enhanced membrane interaction and/or for inhibiting cell wall synthesis.…”

Focal targeting by human β-defensin 2 disrupts localized virulence factor assembly sites in Enterococcus faecalis

“…However, some CAMPs have additional targets that facilitate their toxic effects (40). Particularly well studied are peptides that interact specifically with the peptidoglycan biosynthesis intermediate lipid II at high affinity, including the lantibiotic nisin, fungal defensin plectasin, human neutrophil peptides, and hBD3, allowing them to "dock" at sites of cell-wall synthesis resulting in the sequestration of lipid II away from its functional location and/or resulting in localized membrane pore formation (22,(41)(42)(43)(44)(45). Because nascent PG synthesis, and hence lipid II appearance, occurs in rings emanating from the septal area in ovococci such as E. faecalis, it would not be surprising for lipid II targeting CAMPs to localize to the septal area, as we observe.…”

New Structural Templates for Clinically Validated and Novel Targets in Antimicrobial Drug Research and Development

“…Thus, the lipid II cycle is a highly dynamic process that represents the bottleneck in bacterial cell wall synthesis. Therefore, the lipid II cycle is an ideal target for antibiotics (Breukink and de Kruijff 2006). The first approved antibiotic targeting lipid II was the glycopeptide vancomycin 7 (Scheme 4).…”

“…(Brötz-Oesterhelt and Brunner 2008;Kohanski et al 2010;Lewis 2013;Butler et al 2013b;Wright et al 2014;Bush 2015) (Mullane and Gorbach 2011;Scott 2013;Butler et al 2013b;Zhanel et al 2015Zhanel et al ) (1948 Lipid II and lipid III -The bottlenecks in peptidoglycan and wall teichoic acid synthesis Known, clinically validated targets represent the most promising choice for the development of novel antibiotics, in particular when novel chemical scaffolds that address different binding sites compared to existing drugs break resistance. An excellent example for such a target is lipid II 6 (Scheme 2) (Breukink and de Kruijff 2006;de Kruijff et al 2008), an amphiphilic, membrane-anchored peptidoglycan precursor molecule that is essential for cell membrane functionality.…”

“…The cell walls of all bacteria contain a layer of peptidoglycan, a biopolymer of the alternating amino sugars N-acetylglucosamine (D-NAc-Glu, NAG) and N-acetylmuramic acid (NAc-Mur, NAM), which is modified with pentapeptides of the sequence L-alanyl--D-glutamyl-L-lysyl-D-alanyl-D-alanine (in the case of S. aureus) that is attached to the 3-hydroxy group of the NAc-Mur sugar (Schwartz et al 2001;Breukink and de Kruijff 2006;de Kruijff et al 2008). The cross linkage of the peptides by penicillin binding proteins (PBPs) to macromolecules confers a structural rigidity and mechanical strength that prevents the bacterial protoplast to burst under the osmotic internal pressure.…”