Impact of Multivalence and Self-Assembly in the Design of Polymeric Antimicrobial Peptide Mimics

Abstract

Antimicrobial resistance is an increasingly serious challenge for public health and could result in dramatic negative consequences for the health care sector during the next decades. To solve this problem, antibacterial materials that are unsusceptible toward the development of bacterial resistance are a promising branch of research. In this work, a new type of polymeric antimicrobial peptide mimic featuring a bottlebrush architecture is developed, using a combination of reversible addition–fragmentation chain transfer (RAFT) polymerization and ring-opening metathesis polymerization (ROMP). This approach enables multivalent presentation of antimicrobial subunits resulting in improved bioactivity and an increased hemocompatibility, boosting the selectivity of these materials for bacterial cells. Direct probing of membrane integrity of treated bacteria revealed highly potent membrane disruption caused by bottlebrush copolymers. Multivalent bottlebrush copolymers clearly outperformed their linear equivalents regarding bioactivity and selectivity. The effect of segmentation of cationic and hydrophobic subunits within bottle brushes was probed using heterograft copolymers. These materials were found to self-assemble under physiological conditions, which reduced their antibacterial activity, highlighting the importance of precise structural control for such applications. To the best of our knowledge, this is the first example to demonstrate the positive impact of multivalence, generated by a bottlebrush topology in polymeric antimicrobial peptide mimics, making these polymers a highly promising material platform for the design of new bactericidal systems.

Nano-vehicles give new lease of life to existing antimicrobials

“…Finally, in an interesting study by Laroque, Reifarth et al, AMPs were used not in conjunction with nanoparticles and fibres, but in a 'bottlebrush' architecture, where polymeric side chains are attached to a backbone. This material interfered with the bacterial cell envelope and affected bacterial growth [56]. Similar effects were reported by Zhang et al [57].…”

Biobased polymers derived from itaconic acid bearing clickable groups with potent antibacterial activity and negligible hemolytic activity

“…As an additional advantage, in the majority of the reported synthetic polymers, the problems associated with AMPs such as high cost and poor pharmacokinetic properties have been overcome. However, most synthetic antimicrobial polymers are based on non-degradable backbones, [5][6][7][8] which limit their application in clinical uses as they can be accumulated in the body and exert long term toxicity. Biodegradability is also an important and desired property for many biomedical applications including bioresorbable stents and prosthesis, food packaging and agricultural uses, which also contributes to sustainability by reducing the waste impact of fossil-based polymers.…”

Tuning the Activity of Anoplin by Dendrimerization of Lysine and Lipidation of the N-Terminal

“…However, the tetramer formed a conformation, which is not conducive to antibacterial activity due to its too strong hydrophobicity and large molecular volume. 15 , 16 From the CD data, K-2A-C12, 2K-3A-C10, 2K-3A-C12, 3K-4A-C8, 3K-4A-C10, and 3K-4A-C12 have a higher α-helical content than other analogues in water, but they have lower antimicrobial activity (GM > 42 μM). Therefore, the high α-helical content of anoplin analogues in water may have a negative effect on the antimicrobial activity but no obviously regular effect on hemolytic activity and cytotoxicity.…”