Interest in developing antibacterial polymers as synthetic mimics of host defense peptides (HPDs) has accelerated in recent years to combat antibiotic-resistant bacterial infections. Positively charged moieties are critical in defining the antibacterial activity and eukaryotic toxicity of HDP mimics. Most examples have utilized primary amines or guanidines as the source of positively charged moieties, inspired by the lysine and arginine residues in HDPs. Here, we explore the impact of amine group variation (primary, secondary, or tertiary amine) on the antibacterial performance of HDP-mimicking β-peptide polymers. Our studies show that a secondary ammonium is superior to either a primary ammonium or a tertiary ammonium as the cationic moiety in antibacterial β-peptide polymers. The optimal polymer, a homopolymer bearing secondary amino groups, displays potent antibacterial activity and the highest selectivity (low hemolysis and cytotoxicity). The optimal polymer displays potent activity against antibiotic-resistant bacteria and high therapeutic efficacy in treating MRSA-induced wound infections and keratitis as well as low acute dermal toxicity and low corneal epithelial cytotoxicity. This work suggests that secondary amines may be broadly useful in the design of antibacterial polymers.
Tackling
microbial infection associated with biomaterial surfaces has been
an urgent need. Synthetic β-peptide polymers can mimic host
defense peptides and have potent antimicrobial activities without
driving the bacteria to develop antimicrobial resistance. Herein,
we demonstrate a plasma surface activation-based practical β-peptide
polymer modification to prepare antimicrobial surfaces for biomedical
materials such as thermoplastic polyurethane (TPU), polytetrafluoroethylene,
polyvinyl pyrrolidone, polyvinyl chloride, and polydimethylsiloxane.
The β-peptide polymer-modified surfaces demonstrated effective
killing on drug-resistant Gram-positive and Gram-negative bacteria.
The antibacterial function retained completely even after the β-peptide
polymer-modified surfaces were stored at ambient temperature for at
least 2 months. Moreover, the optimum β-peptide polymer (50:50
DM-Hex)-modified surfaces displayed no hemolysis and cytotoxicity.
In vivo study using methicillin-resistant Staphylococcus
aureus (MRSA)-pre-incubated TPU-50:50 DM-Hex surfaces
for subcutaneous implantation revealed a 3.4-log reduction of MRSA
cells after the implantation for 11 days at the surrounding tissue
of implanted TPU sheet and significant suppression of infection, compared
to bare TPU control. These results imply promising and practical applications
of β-peptide polymer tethering to prepare infection-resistant
surfaces for biomedical materials and devices.
There are diverse membrane permeabilization behaviors of antimicrobial polycations in zwitterionic or charged vesicles; different mechanisms may occur over time.
Potent and selective antifungal agents are urgently needed due to the quick increase of serious invasive fungal infections and the limited antifungal drugs available. Microbial metabolites have been a rich source of antimicrobial agents and have inspired the authors to design and obtain potent and selective antifungal agents, poly(DL‐diaminopropionic acid) (PDAP) from the ring‐opening polymerization of β‐amino acid N‐thiocarboxyanhydrides, by mimicking ε‐poly‐lysine. PDAP kills fungal cells by penetrating the fungal cytoplasm, generating reactive oxygen, and inducing fungal apoptosis. The optimal PDAP displays potent antifungal activity with minimum inhibitory concentration as low as 0.4 µg mL−1 against Candida albicans, negligible hemolysis and cytotoxicity, and no susceptibility to antifungal resistance. In addition, PDAP effectively inhibits the formation of fungal biofilms and eradicates the mature biofilms. In vivo studies show that PDAP is safe and effective in treating fungal keratitis, which suggests PDAPs as promising new antifungal agents.
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