The emergence of antimicrobial resistance has proven to be a serious challenge, resulting in an overwhelming demand for new antimicrobial agents.1,2 Recently, we developed a new class of antimicrobial agents, termed ‘Structurally Nanoengineered Antimicrobial Polypeptide Particles’ (SNAPPs), in the form of star-shaped polypeptides with efficacy against a range of Gram-negative pathogens.3 These star polypeptides were synthesized via ring-opening polymerization of lysine and valine N-carboxyanhydrides. Herein, we report the background study leading to the discovery of the antimicrobial peptide stars. A library consisting of polypeptides of varying composition, copolymer structure, peptide valency, and architecture was developed and screened for antimicrobial activity. Within the library, star polymers with random copolypeptide arms of lysine and valine were found to be the most effective compared to stars with block copolypeptide and homopeptide arms (Figure 1), and demonstrate substantially enhanced activity compared to its linear equivalent while having negligible hemolytic activity. It was postulated that an overall α-helical conformation in a hydrophobic environment, which was not observed for the linear equivalent, contributed to the potency of stars with random copolypeptide arms. The possible therapeutic utility of the star polypeptides were also evaluated by assessing their antimicrobial efficacy in in vivo-mimicking environments and their interactions with physiologically-relevant (bio)molecules. Collectively, the findings demonstrate the potential of the peptide stars as high-performance antibacterial agents. 1. K. Kuroda, G. A. Caputo, Nanomed. Nanobiotechnol. 2013, 5, 49-66. 2. Z. Xu, M. T. Flavin, J. Flavin, Expert Opin. Investig. Drugs 2014, 23, 163-182. 3. S. J. Lam et al., 2015, in revision.

Antimicrobial peptide stars: The road to discovery and development

250th National Meeting (2015)

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