Developments with investigating descriptors for antimicrobial AApeptides and their derivatives

Abstract

The development of multidrug-resistant strains of bacteria resulting from prolonged treatment with conventional antibiotics has necessitated the need for continuous research for better antibiotic strategies. One of these alternatives is evolutionary antimicrobial peptides also known as host-defense peptides (HDPs). HDPs are an integral part of the innate defense system in multicellular eukaryotes. Although HDPs can largely circumvent the persistent problem of antibiotic resistance due to their bacteriolytic membrane mechanism, they have some drawbacks including a low activity profile and protease instability. AApeptides have recently been introduced as a new class of peptidomimetics with resistance to proteolysis, improved activity profile, and limitless possibilities for structural diversity. Furthermore, they have shown excellent antimicrobial activity. Areas covered: This review updates the reader on the latest developments of antimicrobial AApeptides, the various derivatizations, and their development for antimicrobial applications. The most recent findings on the heterogeneous γ-AA backbone are also outlined. Expert opinion: AApeptides have found diverse applications in antimicrobial studies. AApeptides are believed to exhibit bactericidal properties by imitating the membranolytic action of HDPs. They have shown broad-spectrum antimicrobial activity and are active against medicinally relevant drug-resistant pathogens. AApeptides and their derivatives could gain therapeutic relevance in the design and development of antibiotic agents.

Keywords: AApeptides; antibiotic resistance; antimicrobial activity; antimicrobial peptides; antimicrobial peptidomimetics; host-defense peptides (HDPs).

Figure 1.

General structures of α-peptides and AApeptide derivatives, including α-AApeptides, γ-AApeptides, sulfono- γ-AApeptides, and hybrid α/γ-AApeptides.

Figure 2.

(a) Synthesis of α-AApeptide building block; (b) Synthesis of γ-AApeptide building block; Route 1 shows the synthesis of N-alloc γ-AApeptide building blocks. Route 2 should be adopted when chiral side chain, R, is protected with acid-labile groups[60];Alloc: allyloxycarbonyl; (c) Solid Phase Synthesis of α-AApeptides; (d) Solid Phase Synthesis of γ-AApeptides. Adapted with permission from [50] Copyright (2016) American Chemical Society.

Figure 3.

The structures of active α-AApeptides. Adapted with permission from [50] Copyright (2016) American Chemical Society.

Figure 4.

Structures of antimicrobial γ-AApeptides. Adapted with permission from [50] Copyright (2016) American Chemical Society.

Figure 5.

Representative structures of antimicrobial α/γ-AApeptides with heterogenous backbone. Adapted with permission from [80,82] Copyright (2016) American Chemical Society and Copyright (2014) Wiley-VCH Verlag GmbH & Co. KGaA