Lipid II: A central component in bacterial cell wall synthesis and a target for antibiotics

Abstract

a b s t r a c tThe bacterial cell wall is mainly composed of peptidoglycan, which is a three-dimensional network of long aminosugar strands located on the exterior of the cytoplasmic membrane. These strands consist of alternating MurNAc and GlcNAc units and are interlinked to each other via peptide moieties that are attached to the MurNAc residues. Peptidoglycan subunits are assembled on the cytoplasmic side of the bacterial membrane on a polyisoprenoid anchor and one of the key components in the synthesis of peptidoglycan is Lipid II. Being essential for bacterial cell survival, it forms an attractive target for antibacterial compounds such as vancomycin and several lantibiotics. Lipid II consists of one GlcNAcMurNAc-pentapeptide subunit linked to a polyiosoprenoid anchor 11 subunits long via a pyrophosphate linker. This review focuses on this special molecule and addresses three questions. First, why are special lipid carriers as polyprenols used in the assembly of peptidoglycan? Secondly, how is Lipid II translocated across the bacterial cytoplasmic membrane? And finally, how is Lipid II used as a receptor for lantibiotics to kill bacteria?

Conservation of the PTEN catalytic motif in the bacterial undecaprenyl pyrophosphate phosphatase, BacA/UppP

“…In contrast to dolichol biosynthesis, eubacteria synthesize undecaprenyl pyrophosphate (C 55 -PP) which is then dephosphorylated to undecaprenyl monophosphate (C 55 -P), the obligate lipid carrier for peptidoglycan, lipopolysaccharides, the enterobacterial common antigen, capsule polysaccharides and teichoic acid biosynthesis (Bouhss et al, 2008;Cantagrel & Lefeber, 2011;de Kruijff et al, 2008;Lovering et al, 2012;Reusch & Salton, 1984;Swoboda et al, 2010). In addition, undecaprenyl monophosphate is the carrier for N-linked protein glycosylation in prokaryotes (Fig.…”

“…eukaryotes, bacteria and archaea (Calo et al, 2010;Helenius & Aebi, 2004;Jones et al, 2009;Larkin & Imperiali, 2011;Nothaft & Szymanski, 2010;Schwarz & Aebi, 2011;Weerapana & Imperiali, 2006). Monophosphate lipid carriers are also used in the synthesis of bacterial cell envelope polymers such as peptidoglycan, lipopolysaccharides and teichoic acids (Bouhss et al, 2008;Cantagrel & Lefeber, 2011;de Kruijff et al, 2008;Lovering et al, 2012;Reusch & Salton, 1984;Swoboda et al, 2010). As uniquely conserved components of the bacterial cell envelope synthesis and glycosylation pathways, polyisoprenoid lipid carriers are thus essential for life (Hartley & Imperiali, 2012).…”

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

“…(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.…”

Enhancement of antibiotic-activity through complexation with metal ions - Combined ITC, NMR, enzymatic and biological studies

“…[11,12] These metallohydrolases require at least one metal ion in the active site to coordinate to the nucleophile required for hydrolysis. [7][8][9][10][13][14][15][16][17] In recent years, several groups have been…”