Mechanistic insights into hydrophobicity-dependent antimicrobial selectivity of quaternary ammonium poly(oxanorborneneimide) polymers using coarse-grained simulations

Abstract

The rapid rise of antibiotic resistance to small molecule drugs has driven the development of materials that directly target and disrupt bacterial cell membranes. Inspired by antimicrobial peptides (AMPs), synthetic polymers are gaining attention as promising antimicrobial materials because their molecular properties, such as hydrophobicity and charge, can be tuned to enhance selective killing of bacterial versus mammalian cells. Poly(oxanorborneneimide) (PONI) polymers, featuring rigid bicyclic monomer units to mimic the amphiphilicity of AMPs, have exhibited high selectivity against a broad spectrum of Gram-negative and Gram-positive bacteria over human cells depending upon their side chain functionalities. However, the mechanistic basis of this selectivity remains poorly understood, limiting the physiochemical insight needed to efficiently design new PONI polymers with enhanced selectivity. In this study, we present a molecular dynamics (MD) simulation framework to investigate PONI–membrane interactions and extract several mechanistically relevant descriptors correlated with experimentally determined activities. Building upon prior experimental studies, we model four PONI polymers with side chains of increasing hydrophobicity to understand interactions with model E. coli, methicillin-resistant S. aureus (MRSA), and human red blood cell (RBC) membranes. Central to this framework, we develop a generalizable coarse-grained parameterization strategy for PONI polymers within the MARTINI 3 force field to enable simulation of polymer–membrane interactions at experimentally relevant length and timescales. Our simulations reveal that experimental activities against different membranes can be related to the propensity for PONI polymers to insert into the membrane, driven by electrostatic and hydrophobic interactions. We find that differences in membrane lipid composition, particularly strong enrichment of cardiolipin in bacterial membranes, play a critical role in the highly selective interactions of moderately hydrophobic polymers with bacterial versus RBC membranes, in contrast with the non-selective toxicity toward both bacterial and human RBC membranes observed with highly hydrophobic polymers.