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

The rise of antibiotic resistance to small-molecule drugs has driven the
development of materials that directly disrupt bacterial cell membranes.
Inspired by antimicrobial peptides (AMPs), synthetic polymers are gaining
attention as promising antimicrobial materials because their molecular
properties can be tuned to enhance selective killing of bacterial versus
mammalian cells. Poly(oxanorborneneimide) (PONI) polymers have exhibited
high selectivity against a broad spectrum of bacteria over human cells,
depending upon their side chain functionalities. However, the mechanistic
basis of this selectivity remains poorly understood, limiting the design
of new PONI polymers with enhanced selectivity. In this study, we present
a molecular dynamics (MD) simulation framework to investigate
PONI-membrane interactions and extract mechanistically relevant
descriptors correlated with experimentally determined activities. 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. 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 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 composition, particularly enrichment of cardiolipin in bacterial
membranes, play a critical role in the selective interactions of
moderately hydrophobic polymers toward bacterial membranes, in contrast
with the non-selective toxicity toward both bacterial and RBC membranes
observed for highly hydrophobic polymers.