Short Antimicrobial Lipo‐α/γ‐AA Hybrid Peptides

Abstract

The last two decades have seen the rise of antimicrobial peptides (AMPs) to combat emerging antibiotic resistance. Herein we report the solid phase synthesis of short lipidated α/γ-AA hybrid peptides. This family of lipo-chimeric peptidomimetics displays potent and broad-spectrum antimicrobial activity against a range of multi-drug resistant Gram-positive bacteria and Gram-negative bacteria. These lipo-α/γ-AA hybrid peptides also demonstrate high biological specificity, with no hemolytic activity towards red blood cells. Fluorescence microscopy suggests that these lipo-α/γ-AA chimeric peptides can mimic the mode of action of AMPs and kill bacterial pathogens via membrane disintegration. As the composition of these chimeric peptides is simple, therapeutic development may be economically feasible, and amenable for a variety of antimicrobial applications.

The effect of glycine replacement with flexible ω-amino acids on the antimicrobial and haemolytic activity of an amphipathic cyclic heptapeptide

“…ω-amino and α,ω-diamino acids) affected the antimicrobial and haemolytic activity of a model amphipathic cyclic heptamer and, more in general, whether this could represent an effective optimization approach for cyclic antimicrobial peptides. This investigation therefore expands the scope of previous studies conducted on the backbone of linear AMPs [11][12][13]. We report that such modifications proved as or more effective than any other ring substitution in increasing the antimicrobial activity and reducing the toxicity of the studied cyclic heptapeptide.…”

The Development of Antimicrobial γ-Aapeptides

“…We hypothesized that short antimicrobial γ-AApeptides may also have potential application in antimicrobial field. As such, a focused library was synthesized by utilizing a hybrid backbone of canonical α-amino acid residues fused with γ-AApeptides (Figure 4 & Table 1) [41]. As anticipated, γ8 [41] exerts bactericidal activity rapidly by mimicking HDPs without showing any hemolytic activity at concentrations up to 350 μgml -1…”

“…The results show that they can mimic HDPS and exhibit broad-spectrum activ- A helical scaffold of γ9 is also shown, in which red dots represent hydrophobic groups, and blue dots represent hydrophilic groups. Data taken from [37][38][39][40][41][42][43].…”

“…Again, studies including time kill and fluorescence microscopy suggested that lipo-α/γ-AApeptides can mimic the mode of action of HDPs and kill bacterial pathogens via membrane disintegration. In addition, lipo-α/γ-AApeptides also benefit from a more economical synthetic p rocess when compared with previous γ-AApeptides [41].…”

“…In addition, they also harness immune response and inhibit lipopolysaccharide (LPS)-activated Toll-like receptor 4 (TLR4) signaling [36]. In addition, γ-AApeptides have shown promise as potential antimicrobial agents [37][38][39][40][41][42][43]. Recently, γ-AApeptides exhibit comparable or enhanced performance compared with ciprofloxacin in the prevention of biofilm formation of both Gram-positive and Gram-negative bacteria [44].…”