Structural variations of the cell wall precursor lipid II in Gram-positive bacteria — Impact on binding and efficacy of antimicrobial peptides

Abstract

Antimicrobial peptides (AMPs) are natural antibiotics produced by virtually all living organisms. Typically, AMPs are cationic and amphiphilic and first contacts with target microbes involve interactions with negatively charged components of the cell envelope such as lipopolysaccharide (LPS), and wall- or lipoteichoic acids (WTA, LTA). The importance of charge-mediated interactions of AMPs with the cell envelope is reflected by effective microbial resistance mechanisms which are based on reduction of the overall charge of these polymers. The anionic polymers are linked in various ways to the stress-bearing polymer of the cell envelope, the peptidoglycan, which is made of a highly conserved building block, a disaccharide-pentapeptide moiety that also contains charged residues. This structural element, in spite of its conservation throughout the bacterial world, can undergo genus- and species-specific modifications that also impact significantly on the overall charge of the cell envelope and on the binding affinity of AMPs. The modification reactions involved largely occur on the membrane-bound peptidoglycan building block, the so-called lipid II, which is a most prominent target for AMPs. In this review, we focus on modifications of lipid II and peptidoglycan and discuss their consequences for the interactions with various classes of AMPs, such as defensins, lantibiotics and glyco-(lipo)-peptide antibiotics. This article is part of a Special Issue entitled: Bacterial Resistance to Antimicrobial Peptides.

Recent Developments in Antimicrobial Polymers: A Review

“…One of the strategies followed by several drugs is interfering with the synthesis of the peptidoglycan. An important precursor of the peptidoglycan synthesis is the lipid II, which was shown to be an attractive target of antibacterial compounds, such as AMPs [53]. In addition, a recent study also demonstrated that the precursors of peptidoglycan, lipids III and IV, are also targets.…”

Inhibition of Staphylococcus aureus Cell Wall Biosynthesis by Desleucyl-Oritavancin: a Quantitative Peptidoglycan Composition Analysis by Mass Spectrometry

“…Unlike the Edman degradation product of vancomycin, which is devoid of any activity, des-Ori retains potent antimicrobial activities against both vancomycin-susceptible and -resistant pathogens despite the damaged D-Ala-D-Ala binding site (28,29). This activity is mediated by the secondary binding site, which allows des-Ori binding to cross-linked PG in the cell wall (4, 7), as well as increased binding affinity to lipid II that has a pentaglycine bridge attached (30).…”

New Found Hope for Antibiotic Discovery: Lipid II Inhibitors

“…The pentapeptide l ‐Ala‐ d ‐ γ ‐Glu‐ l ‐Lys‐ d ‐Ala‐ d ‐Ala is typically present in most Gram‐positive pathogens . Cross‐linking of the glycan chains is then achieved through side‐chain‐to‐backbone amide bond formation between strands of pentapeptide domains …”

“…Bacterial cell wall biosynthesis is highly complex, with multiple components and numerous tightly coordinated enzymatic reactions (Figure ) . The two‐stage process of peptidoglycan subunit synthesis begins with the assembly of UDP‐MurNAc‐pentapeptide precursor from UDP‐GlcNAc through a series of steps catalysed by MurA‐F synthetases in cytoplasmic side .…”

“…UDP‐MurNAc‐pentapeptide is then transferred by MraY translocase to the 11‐subunit membrane‐embedded undecaprenyl phosphate, thereby producing an intermediate called lipid I. Following the coupling of GlcNAc to lipid I, lipid II is formed which carries the complete peptidoglycan subunit (GlcNAc‐MurNAc‐pentapeptide) that is attached to undecaprenyl phosphate by a pyrophosphate moiety . During the second stage, lipid II is flipped by MurJ or FtsW flippase to the periplasmic side of inner membrane .…”