De Novo Design of Antimicrobial Polymers, Foldamers, and Small Molecules: From Discovery to Practical Applications

Abstract

Conspectus Antimicrobial peptides (AMPs) provide protection against a variety of pathogenic bacteria and are, therefore, an important part of the innate immune system. Over the last decade, there has been considerable interest in developing AMPs as intravenously administered antibiotics. However, despite extensive efforts in the pharmaceutical and biotechnology industry, it has proven difficult to achieve this goal. While researchers have solved some relatively simple problems such as susceptibility to proteolysis, more severe problems have included the expense of the materials, toxicity, limited efficacy, and limited tissue distribution. In this Account, we describe our efforts to design and synthesize “foldamers”-- short sequence-specific oligomers based on arylamide and β-amino acid backbones, which fold into well-defined secondary structures-- that could act as antimicrobial agents. We reasoned that small “foldamers” would be less expensive to produce than peptides, and might have better tissue distribution. It should be easier to fine-tune the structures and activities of these molecules to minimize toxicity. Because the activities of many AMPs depends primarily on their overall physicochemical properties rather than the fine details of their precise amino acid sequences, we have designed and synthesized very small “coarse-grained” molecules, which are far simpler than naturally produced AMPs. The molecular design of these foldamers epitomizes the positively charged amphiphilic structures believed to be responsible for the activity of AMPs. The designed oligomers show greater activity than the parent peptides. They have also provided leads for novel small molecule therapeutics that show excellent potency in animal models for multi-drug resistant bacterial infections. In addition, such molecules can serve as relatively simple experimental systems for investigations aimed at understanding the mechanism of action for this class of antimicrobial agents. The foldamers’ specificity for bacterial membranes relative to mammalian membranes appears to arise from differences in membrane composition and physical properties between these cell types. Furthermore, because experimental coarse-graining provided such outstanding results, we developed computational coarse-grained models to enable molecular dynamic simulations of these molecules with phospholipid membranes. These simulations allow investigation of larger systems for longer times than conventional molecular dynamics simulations, allowing us to investigate how physiologically relevant surface concentrations of AMP mimics affect the bilayer structure and properties. Finally, we apply the principles discovered through this work to the design of inexpensive antimicrobial polymers and materials.

Molecular Biosafety

“…Therapeutic use of some synthetic versions of AMPS is being actively explored with the aim of optimizing efficacy while minimizing the limitations of endogenous AMPs (Rozgony et al, 2009;Tew et al, 2010). Because of the complexity of the vertebrate immune system, however, use of synthetic AMPS as antimicrobial agents will need to be carefully tested to ensure that such treatments do not result in negative unforeseen impacts on the host's immune response.…”

“…These include bioavailability (limited tissue distribution), stability, potential immunogenicity, potential eukaryotic toxicity, and high production costs (Liu et al, 2010;Rotem & Mor, 2009;Tew et al, 2010). Many laboratories are developing synthetic AMPs and peptidomimetics in an attempt to overcome these limitations of natural AMPs while maximizing the antimicrobial effects.…”

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.…”

Dark Antimicrobial Mechanisms of Cationic Phenylene Ethynylene Polymers and Oligomers against Escherichia coli

“…In recent years, the appearance of "superbugs", which are resistant to almost all commercial antibiotics, has been a critical worldwide healthcare issue [2,3]. As a result, developing new classes of efficient antimicrobial agents has been the focus of significant research efforts during the last decade [4][5][6][7][8][9]. Since the discovery of the antimicrobial properties of poly(phenylene ethynylene) (PPE)-based cationic conjugated polyelectrolytes (CPEs) [10], a wide range of structurally similar polymeric CPEs and oligomeric OPEs (oligo-phenylene ethynylenes) have been synthesized [11][12][13][14][15][16].…”