Synthetic mimics of antimicrobial peptides

Abstract

Infectious diseases and antibiotic resistance are now considered the most imperative global healthcare problem. In the search for new treatments, host defense, or antimicrobial, peptides have attracted considerable attention due to their various unique properties; however, attempts to develop in vivo therapies have been severely limited. Efforts to develop synthetic mimics of antimicrobial peptides (SMAMPs) have increased significantly in the last decade, and this review will focus primarily on the structural evolution of SMAMPs and their membrane activity. This review will attempt to make a bridge between the design of SMAMPs and the fundamentals of SMAMP-membrane interactions. In discussions regarding the membrane interaction of SMAMPs, close attention will be paid to the lipid composition of the bilayer. Despite many years of study, the exact conformational aspects responsible for the high selectivity of these AMPs and SMAMPs toward bacterial cells over mammalian cells are still not fully understood. The ability to design SMAMPs that are potently antimicrobial, yet nontoxic to mammalian cells has been demonstrated with a variety of molecular scaffolds. Initial animal studies show very good tissue distribution along with more than a 4-log reduction in bacterial counts. The results on SMAMPs are not only extremely promising for novel antibiotics, but also provide an optimistic picture for the greater challenge of general proteomimetics.

Engineering Microbial Physiology with Synthetic Polymers: Cationic Polymers Induce Biofilm Formation inVibrio choleraeand Downregulate the Expression of Virulence Genes

“…Having identified that P1 was able to sequester V. cholerae into clusters, we then evaluated the viability of the pathogen in the presence of this polymer. Cationic polymers are commonly reported as bactericidal materials, [8][9][10][11] although small changes in structure and dose can result in significant differences in activity and toxicity. This effect is often microbe specific, and in particular P1 has been reported to have a minimum inhibitory concentration of 10-25 μg/mL for Escherichia coli, 30 while showing no effect on V. harveyi's viability and growth at concentations as high as 500 μg/mL.…”

“…Not suprisingly, P1 compromised membrane integrity of the mammalian cells at the highest concentrations tested (≥ 50 μg/mL), in agreement with the reported toxicity of cationic materials. [8][9][10][11] However, we anticipated that this toxicity could be reduced following incubation with bacteria, as the cationic charge will not be exposed following interaction with the pathogen's negatively charged membrane. This was indeed the case when we evaluated the potential of this polymer to inhibit colonisation by V. cholerae of this intestinal epithelial cell line (Fig.…”

“…In particular novel approaches that can replace or enhance current antimicrobials are highly desired. [3][4][5] Polymeric materials have often been postulated as alternatives in these areas, either as delivery vehicles for antimicrobials, 6,7 or as novel antimicrobial polymers, [8][9][10][11] and materials that can interfere with microbial adhesion. [12][13][14][15] Polymeric materials are especially attractive in these applications because of their multivalency, ease of manufacturing and the potential to precisely control polymer length and composition.…”

Functional foldamers that target bacterial membranes: The effect of charge, amphiphilicity and conformation

“…[1][2][3][4][5] A foldamer can be defined as "a discrete oligomer that folds into a conformationally ordered state in solution", and contemporary research has shown that a number of foldamer constructs (in particular, antimicrobial peptides (AMPs)) can interact with, and disrupt, bacterial cell membranes thus making these agents valid candidates for future therapeutics, particularly if selectivity over host cells can be achieved. [6][7][8][9][10][11][12][13][14] In light of this need, our research group has recently developed a range of AMP-influenced mimetics which are based on a foldamer scaffold, under the presumption that control over antimicrobial properties could be obtained by fine-tuning the molecules' charge, amphiphilicity and conformation. 8,[10][11][12][13][15][16][17][18][19] Previous efforts have looked at the influence of foldamer length and conformation on membrane interaction, [15][16][17][18][19] but as yet, the effects of charge and thereby amphiphilicity have not been studied against bacterial membranes by us.…”

Peptides extracted from <i>Artemisia herba alba</i> have antimicrobial activity against foodborne pathogenic gram-positive bacteria

“…However, to date, only their cognates from bacteria and mammals as well as their synthetic mimics enjoy practical applications in human infectious disease treatments as novel antibiotics against multi-drug resistant pathogens; or in biopreservation as novel food additives (Mills et al, 2011;Som et al, 2008;Yeung et al, 2011).…”