The Study and Application of Membrane Binding Supramolecular Self-associating Amphiphiles

With the looming threat of antimicrobial resistance (AMR) and the distinct absence of new antimicrobial agents on the market, the development of novel therapeutic treatments against AMR bacteria is vital. The work detailed herein demonstrates the potential for supramolecular self-associating amphiphiles (SSAs) to act as the first anionic antimicrobial potentiator of novobiocin (52) and rifampicin (53) against ESKAPE pathogen Pseudomonas aeruginosa. The most effective combination offered a dramatic 8-fold decrease of the MIC of novobiocin (52), from 3.2 mM to 0.4 mM in the presence of a non-inhibitory SSA concentration. Extensive physicochemical characterisation of SSA/antimicrobial interactions offer explanations for the observed synergistic behaviour.

This thesis validates the hypothesis that SSAs are bacterial membrane disruptors through the employment of fluorescence spectroscopy. The urea benzothiazole SSAs were found to exhibit the highest level of broad range vesicle lysis, however a lack of correlation was observed between vesicle lysis and selective SSA: phospholipid interaction. The ability for SSAs to induce membrane fluidity was explored, revealing the carboxylate moiety over a sulfonate can selectively increase the membrane fluidity of bacterial model membranes over eukaryotic. Finally, a patch clamp method was optimised, providing insight into the potential transport mechanism of SSAs in the presence of an anionophore.