Abstract
Multidrug resistance (MDR) to conventional antibiotics is one of the most urgent global health threats, necessitating the development of effective and biocompatible antimicrobial agents that are less inclined to provoke resistance. Structurally nanoengineered antimicrobial peptide polymers (SNAPPs) are a novel and promising class of such alternatives. These star-shaped polymers are made of a dendritic core with multiple arms made of copeptides with varying amino acid sequences. Through a comprehensive set of in vivo experiments, we previously showed that SNAPPs with arms made of random blocks of lysine (K) and valine (V) residues exhibit sub-μM efficacy against Gram-negative and Gram-positive bacteria tested. Cryo-TEM images suggested pore formation by a SNAPP with random block copeptide arms as one of their modes of actions. However, the molecular mechanisms responsible for this mode of action of SNAPPs are not fully understood. To address this gap, we employed an atomistic molecular dynamics simulation technique to investigate the influence of three different sequences of amino acids, namely (1) alt-block KKV, (2) ran-block, and (3) diblock motifs on the secondary structure of their arms and SNAPP's overall configuration as well as their interactions with lipid bilayer. We, for the first time, identified a step-by-step mechanism through which alt-block and random SNAPPs interact with lipid bilayer and lead to "pore formation", hence, cell death. These insights provide a strong foundation for further optimization of the chemical structure of SNAPPs for maximum performance against MDR bacteria, therefore offering a promising avenue for addressing antibiotic resistance and the development of effective antibacterial agents.
Published Version
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