Lipo-γ-AApeptides as a New Class of Potent and Broad-Spectrum Antimicrobial Agents

Abstract

There is increasing demand to develop antimicrobial peptides (AMPs) as next generation antibiotic agents, as they have the potential to circumvent emerging drug resistance against conventional antibiotic treatments. Non-natural antimicrobial peptidomimetics are an ideal example of this, as they have significant potency and in vivo stability. Here we report for the first time the design of lipidated γ-AApeptides as antimicrobial agents. These lipo-γ-AApeptides show potent broad-spectrum activities against fungi and a series of Gram-positive and Gram-negative bacteria, including clinically relevant pathogens that are resistant to most antibiotics. We have analyzed their structure-function relationship and antimicrobial mechanisms using membrane depolarization and fluorescent microscopy assays. Introduction of unsaturated lipid chain significantly decreases hemolytic activity and thereby increases the selectivity. Furthermore, a representative lipo-γ-AApeptide did not induce drug resistance in S. aureus, even after 17 rounds of passaging. These results suggest that the lipo-γ-AApeptides have bactericidal mechanisms analogous to those of AMPs and have strong potential as a new class of novel antibiotic therapeutics.

The Development of Antimicrobial γ-Aapeptides

“…We Table 1) [38]. It is remarkable that both γ3 and γ4 are even more potent and broad-spectrum than the previously reported linear sequence γ2 [37] toward the Gram-negative bacterium P. aeruginosa.…”

“…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].…”

“…It is remarkable that both γ3 and γ4 are even more potent and broad-spectrum than the previously reported linear sequence γ2 [37] toward the Gram-negative bacterium P. aeruginosa. In addition, lipo-linear γ-AApeptides exert bactericidal ability through its membrane disruption properties like HDPs, as evidenced by fluorescence microscopy, membrane depolarization and drug resistance s tudies [38].…”

“…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].…”

Peptidomimetics as Antimicrobial Agents

“…AApeptides are a new class of peptidomimetics developed in our group recently in order to expand the application of peptidomimetics in chemical biology [72][73][74][75][76][77][78][79]. They are termed AApeptides because they are composed of N-acylated-N-aminoethyl amino acid units that are derived from the chiral PNA backbone.…”