Rational design of biodegradable thermoplastic polyurethanes for tissue repair

Pathogenic microorganisms are considered to a major threat to human health, impinging on multiple sectors including hospitals, dentistry, food storage and packaging, and water contamination. Due to the increasing levels of antimicrobial resistance shown by pathogens, often caused by long-term abuse or overuse of traditional antimicrobial drugs, new approaches and solutions are necessary. In this area, antimicrobial polymers are a viable solution to combat a variety of pathogens in a number of contexts. Indeed, polymers with intrinsic antimicrobial activities have long been an intriguing research area, in part, due to their widespread natural abundance in materials such as chitin, chitosan, carrageen, pectin, and the fact that they can be tethered to surfaces without losing their antimicrobial activities. In addition, since the discovery of the strong antimicrobial activity of some synthetic polymers, much work has focused on revealing the most effective structural elements that give rise to optimal antimicrobial properties. This has often been synthesis targeted, with the generation of either new polymers or the modification of natural antimicrobial polymers with the addition of antimicrobial enhancing modalities such as quaternary ammonium or guanidinium groups. In this review, the growing number of polymers showing intrinsic antimicrobial properties from the past decade are highlighted in terms of synthesis; often based on post-synthesis modification and their utilization. This includes as surface coatings, for example on medical devices, such as intravascular catheters, orthopaedic implants and contact lenses, or directly as antibacterial agents (specifically as eye drops). Surface functionalisation with inherently antimicrobial polymers is highlighted and has been achieved via various techniques, including surface-bound initiators allowing RAFT or ATRP surface-based polymerization, or via physical immobilization such as by layer-by-layer techniques. This article also covers the mechanistic modes of action of intrinsic antimicrobial polymers against bacteria, viruses, or fungi.

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Polymers showing intrinsic antimicrobial activity.

Pyrimidine-conjugated fluoroquinolones as new potential broad-spectrum antibacterial agents.

Bacterial biofilms formed by pathogens are known to be hundreds of times more resistant to antimicrobial agents than planktonic cells, making it extremely difficult to cure biofilm-based infections despite the use of antibiotics, which poses a serious threat to human health. Therefore, there is an urgent need to develop promising alternative antimicrobial therapies to reduce the burden of drug-resistant bacterial infections caused by biofilms. As natural enemies of bacteria, bacteriophages (phages) have the advantages of high specificity, safety and non-toxicity, and possess great potential in the defense and removal of pathogenic bacterial biofilms, which are considered to be alternatives to treat bacterial diseases. This work mainly reviews the composition, structure and formation process of bacterial biofilms, briefly discusses the interaction between phages and biofilms, and summarizes several strategies based on phages and their derivatives against biofilms and drug-resistant bacterial infections caused by biofilms, serving the purpose of developing novel, safe and effective treatment methods against biofilm-based infections and promoting the application of phages in maintaining human health.

/pdf/phages-against-pathogenic-bacterial-biofilms-and-biofilm-17hy0852.pdf

Phages against Pathogenic Bacterial Biofilms and Biofilm-Based Infections: A Review

New antifungals are urgently needed to combat invasive fungal infections, due to limited types of available antifungal drugs and frequently encountered side effects, as well as the quick emergence of drug-resistance. We previously developed amine-pendent poly(2-oxazoline)s (POXs) as synthetic mimics of host defense peptides (HDPs) to have antibacterial properties, but with poor antifungal activity. Hereby, we report the finding of short guanidinium-pendent POXs, inspired by cell-penetrating peptides, as synthetic mimics of HDPs to display potent antifungal activity, superior mammalian cells vs fungi selectivity, and strong therapeutic efficacy in treating local and systemic fungal infections. Moreover, the unique antifungal mechanism of fungal cell membrane penetration and organelle disruption explains the insusceptibility of POXs to antifungal resistance. The easy synthesis and structural diversity of POXs imply their potential as a class of promising antifungal agents.

Short Guanidinium-Functionalized Poly(2-oxazoline)s Displaying Potent Therapeutic Efficacy on Drug-Resistant Fungal Infections.

Over 80% of all chronic bacterial infections in humans are associated with biofilms, which are surface-associated bacterial communities encased within a secreted exopolysaccharide matrix that can provide resistance to environmental and chemical insults. Biofilm formation triggers broad adaptive changes in the bacteria, allowing them to be almost 1000-fold more resistant to conventional antibiotic treatments and host immune responses. The failure of antibiotics to eliminate biofilms leads to persistent chronic infections and can promote the development of antibiotic-resistant strains. Therefore, there is an urgent need to develop agents that effectively prevent biofilm formation and eradicate established biofilms. Herein, we present water-soluble synthetic peptidomimetic polyurethanes that can disrupt surface established biofilms of Pseudomonas aeruginosa, Staphylococcus aureus, and Escherichia coli, all of which show tolerance to the conventional antibiotics polymyxin B and ciprofloxacin. Furthermore, while these polyurethanes show poor antimicrobial activity against planktonic bacteria, they prevent surface attachment and stimulate bacterial surface motility to inhibit biofilm formation of both Gram-positive and Gram-negative bacteria at subinhibitory concentrations, without being toxic to mammalian cells. Our results show that these polyurethanes show promise as a platform for the development of therapeutics that target biofilms and modulate surface interactions of bacteria for the treatment of chronic biofilm-associated infections and as antibiofilm agents.

Allison Ferrell

Papers

Peptidomimetic Polyurethanes Inhibit Bacterial Biofilm Formation and Disrupt Surface Established Biofilms.