Recent Approaches in Design of Peptidomimetics for Antimicrobial Drug Discovery Research

Abstract

Resistant pathogenic microbial strains are emerging at a rate that far exceeds the pace of new anti-infective drug development. In order to combat resistance development, there is pressing need to develop novel class of antibiotics having different mechanism of action in comparison to existing antibiotics. Antimicrobial peptides (AMPs) have been identified as ubiquitous components of innate immune system and widely regarded as a potential source of future antibiotics owing to a remarkable set of advantageous properties ranging from broad spectrum of activity to low propensity of resistance development. However, AMPs present several drawbacks that strongly limit their clinical applicability as ideal drug candidates such as; poor bioavailability, potential immunogenicity and high production cost. Thus, to overcome the limitations of native peptides, peptidomimetic becomes an important and promising approach. The different research groups worldwide engaged in antimicrobial drug discovery over the past decade have paid tremendous effort to design peptidomimetics. This review will focus on recent approaches in design of antimicrobial peptidomimetics their structure-activity relationship studies, mode of action, selectivity & toxicity.

Derivatives of the Mouse Cathelicidin-Related Antimicrobial Peptide (CRAMP) Inhibit Fungal and Bacterial Biofilm Formation

“…Moreover, they are widely regarded as a potential source of future antibiotics owing to a remarkable set of advantageous properties ranging from a broad spectrum of activity to a low propensity for resistance development (17). The major human cationic host defense peptide is LL-37 (Table 1).…”

Arginine-containing peptides as potent inhibitors of VIM-2 metallo-β-lactamase

“…It is important to point out in this connection that compounds of (poly)cationic nature are not unprecedented as antibacterials. Indeed, aminoglycosides and small cationic antimicrobial peptides are naturally occurring antibacterial agents, with the latter class of compounds being regarded as an emerging source of new antimicrobials [84,85]. Furthermore, to overcome some of their drawbacks (e.g., susceptibility of protease-induced cleavage), peptidomimetics are A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT 28 currently being explored with some of them in clinical trials [84][85][86].…”

“…Indeed, aminoglycosides and small cationic antimicrobial peptides are naturally occurring antibacterial agents, with the latter class of compounds being regarded as an emerging source of new antimicrobials [84,85]. Furthermore, to overcome some of their drawbacks (e.g., susceptibility of protease-induced cleavage), peptidomimetics are A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT 28 currently being explored with some of them in clinical trials [84][85][86]. In addition, it is noteworthy that guanidine-containing compounds including small peptides and peptidomimetics harbouring one or more guanidino or arginine moieties are of immense interest as drugs targeting a variety of disorders and diseases [87].…”

Peptoids for biomaterials science

“…21,22 The biorecognition abilities of peptoids have been demonstrated through two decades of peptoid therapeutics research, protein-binding sequence discovery, and secondary structure design, which have been recently reviewed elsewhere. 10,15,[24][25][26][27] As originally envisioned, 7 many bioactive sequences have been discovered by screening peptoid libraries. 8,13 These include antimicrobial peptoidsÑa significant area of peptoid research discussed in recent reviews.…”

“…8,13 These include antimicrobial peptoidsÑa significant area of peptoid research discussed in recent reviews. 10,25,27 Recent studies have also demonstrated peptoid sequences potentially useful in diagnosing or treating amyloid diseases.…”