Dicarboxylate and dicarboxylic acid appended supramolecular self-associating amphiphiles as antimicrobial agents against high priority bacterial pathogens

Abstract

Antimicrobial resistance remains a significant global health challenge. Supramolecular self-associating amphiphiles (SSAs) represent a promising class of compounds for development as antimicrobial agents, offering tuneable self-assembly properties alongside phospholipid membrane-targeting capabilities. Here we evaluate a series of 10 chiral SSAs, incorporating either urea-dicarboxylic acid or urea-dicarboxylate functional groups for the first time. This series of compounds has been designed to investigate how structural features including chirality, positioning of multiple polar functionalities, hydrophobicity, lipophobicity and hydrogen bond donor/acceptor activity effects not only physicochemical properties, such as self-associative aggregate formation, but also antimicrobial activity against the high threat priority pathogens Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii, Staphylococcus aureus, Enterococcus faecalis and Enterococcus faecium. Finally we perform initial in vitro ADME studies to assess the potential for this sub-class of SSAs to be developed as antibiotics.