Host Defense Peptide-Mimicking Polymers and Polymeric-Brush-Tethered Host Defense Peptides: Recent Developments, Limitations, and Potential Success

Abstract

Amphiphilic antimicrobial polymers have attracted considerable interest as structural mimics of host defense peptides (HDPs) that provide a broad spectrum of activity and do not induce bacterial-drug resistance. Likewise, surface engineered polymeric-brush-tethered HDP is considered a promising coating strategy that prevents infections and endows implantable materials and medical devices with antifouling and antibacterial properties. While each strategy takes a different approach, both aim to circumvent limitations of HDPs, enhance physicochemical properties, therapeutic performance, and enable solutions to unmet therapeutic needs. In this review, we discuss the recent advances in each approach, spotlight the fundamental principles, describe current developments with examples, discuss benefits and limitations, and highlight potential success. The review intends to summarize our knowledge in this research area and stimulate further work on antimicrobial polymers and functionalized polymeric biomaterials as strategies to fight infectious diseases.

Keywords: antibiotic resistance; antimicrobial polymers; biofilms; host defense peptides; polymer brush.

Figure 7

Examples of antibiofilm cationic HDP-mimicking polymers. (a) Cationic antimicrobial β-peptide polymer (20:80 Bu:DM) [123,124], and (b) a dextran-block methacrylate-based nanoparticle copolymer [128].

Figure 1

Examples of HDPs with diverse structures. The molecular models were reproduced from the RCSB Protein Databank (http://www.rcsb.org/pdb/home/home.do). β-defensin 2, 1W2E; magainin 2, 2MAG; α-defensin 5, 1ZMP; Indolicidin, 1G89; Snakin 1, 5E5Q.

Figure 2

Evolution of antimicrobial polymers from HDPs. Magainin 2, as an example of an HDP, shows the hydrophobic and cationic domains. In the centre are examples of antimicrobial polymers, and on the right are examples of the described strategies of monomers connectivity in polymers, (block and random), where green and purple circles represent cationic and hydrophobic monomers, respectively.

Figure 3

The diagram shows the influence of cationic/hydrophobic balance in the biological activity and toxicity of HDP-mimicking polymers.

Figure 4

Beyond the amphiphilic balance of antimicrobial polymers. (a) Stereochemistry alters the activity of nylon-3 copolymer [89] and (b) an example of homopolymers with only cationic subunits (P34) but potent antibacterial activity and low toxicity against RBCs [90].

Figure 5

Ternary HDP-mimicking polymers. The introduction of neutral/hydrophilic groups/spacer, as shown, led to a significant reduction in hemolysis. (a) Poly-norbornene polymer incorporated with PEG [97], (b) introducing polar or uncharged units to the nylon-3 copolymers [98], (c) replacement of hydrophobic group with a hydrophilic group in a methacrylate-based polymer [99] and (d) introduction of a polar group as a spacer between the cationic and hydrophobic subunit of a methacrylate-based antimicrobial polymer [102].

Figure 6

Examples of newly reported polymer mimics of HDPs. (a) mimicking amino acid residues on the backbone of the PEG chain and developing PEGtides, (b) glycine-like backbone substituent poly-2-oxazoline, (c) a new class of antimicrobial nanomaterials referred to as structurally nanoengineered antimicrobial peptide polymers (SNAPPs).

Figure 8

An example of biodegradable cationic amphiphilic polycarbonates-based polymer [133].

Figure 9

Representation of polymer brush integrated HDP on a substrate.