Engineering Approaches for the Development of Antimicrobial Peptide-Based Antibiotics

Abstract

Antimicrobial peptides (AMPs) have received increasing attention as potential alternatives for future antibiotics because of the rise of multidrug-resistant (MDR) bacteria. AMPs are small cationic peptides with broad-spectrum antibiotic activities and different action mechanisms to those of traditional antibiotics. Despite the desirable advantages of developing peptide-based antimicrobial agents, the clinical applications of AMPs are still limited because of their enzymatic degradation, toxicity, and selectivity. In this review, structural modifications, such as amino acid substitution, stapling, cyclization of peptides, and hybrid AMPs with conventional antibiotics or other peptides, will be presented. Additionally, nanodelivery systems using metals or lipids to deliver AMPs will be discussed based on the structural properties and action mechanisms of AMPs.

Mycobacterium tuberculosis cell-wall and antimicrobial peptides: a mission impossible?

“…In the design or redesign of AMPs, the ability of bacteria to develop resistance mechanisms to evade them must be considered. The killing ability against bacteria can be achieved by modifying AMPs through strategies such as structural change, amino acid substitution, conjugation with cell-penetration peptides (CPPs), terminal acetylation and amidation, modifying AMPs with organometallic agents and encapsulation with nanoparticles in order to improve the antimicrobial efficacy, reduce toxicity, and accomplish local delivery of AMPs, as reviewed in ( 135 , 170 , 171 ).…”

Lipidation of Naturally Occurring α-Helical Antimicrobial Peptides as a Promising Strategy for Drug Design

“…Thus, the amphipathic structure and the overall positive charge of AMPs determine their mode of action. Cationic AMPs are attracted to the negatively charged bacterial cell membranes and interrupt their structures according to the barrel stave, carpet or toroidal models [ 12 , 13 ]. Besides membranolytic activity, some AMPs can also penetrate the cell membranes in a non-invasive way and interact with internal molecular targets, inhibiting the biosynthesis of the membrane components [ 5 ] or affecting the process of the replication of the genetic material of the microorganisms [ 14 , 15 , 16 ].…”

“…The latter could also shed a light on the capability of AMPs to penetrate the peptidoglycan and lipopolysaccharide layers of Gram-positive and Gram-negative bacteria, respectively. Self-assembly often results in increased stability and proteolytic resistance of antimicrobial peptides [ 12 ], which leads to a higher concentration of AMPs in the target sites and consequently to more efficient elimination of pathogens [ 13 ]. Moreover, it may have an impact on peptide selectivity by reducing the effective peptide hydrophobicity and thus the affinity toward membranes composed of zwitterionic lipids (such as the outer layer of healthy eukaryotic cell membranes) [ 23 ].…”

Bacterial susceptibility and resistance to modelin-5

“…Despite the clear therapeutic potential of AMPs, a number of factors have impeded the full realisation of this potential and in response a number of strategies to improve their efficacy have been employed, 23,24 including the production of synthetic, designed peptides. 25 A major example of these designed AMPs is the C-terminally amidated peptide, modelin-5 (M5-NH 2 ), which is the archetypic member of the modelin family of AMPs.…”