Towards understanding interactions between supramolecular antimicrobial surfactants and microbial membranes

Antimicrobial resistance (AMR) is one of the biggest threats to global health, with the relentless evolution of resistance mechanisms being the greatest arms race. New methods of treatment of these AMR bacteria are required, bypassing resistance mechanisms, allowing for a new generation of supramolecular antimicrobial agents to arise. One avenue of target is the phospholipid membrane, which differs in composition to eukaryotic membranes. The first series of compounds detailed herein show that changing the structure of the compound affects the physicochemical properties, material characteristics, membrane interaction profile, and antimicrobial/antibiofilm properties. It was determined that lysis and membrane adhesion of these compounds occur through many modes of action. The toxicity profile of these compounds was determined using the model organism Caenorhabditis elegans, where no toxicity was observed. A second series of compounds were designed to target Candida Spp., Pseudomonas aeruginosa (P. aeruginosa) and polymicrobial biofilms of the two species. Physicochemical and membrane interaction studies were undertaken, and initial structure activity relationships were formed linking increased hydrogen bond donor acidity with increased antibiofilm activity. Co-formulation of these compounds produced interesting results, with some increased activity against Candida auris polymicrobial biofilms. One of these compounds was taken forward for in vitro DMPK studies and displayed a druggable profile. Finally, the effect of AMR on the phospholipid membrane was determined using two strains and five isogenic mutants of P. aeruginosa. The antimicrobial activity of three sulfobetaine zwitterionic surfactants were determined on this panel of P. aeruginosa and novel mode of action was determined through molecular level interactions with extracted phospholipids from these bacteria. This work gives new insight into the molecular level interactions between antimicrobials and bacteria, enabling future drug discovery and development pathways within the AMR field.