Anionic Self-Assembling Supramolecular Enhancers of Antimicrobial Efficacy against Gram-Negative Bacteria

As a result of the looming antimicrobial resistance crisis, there is an urgent need for novel antimicrobial treatments. This is particularly true for hard-to-treat Gram-negative bacteria, as many antimicrobial agents are unable to cross the cell membrane to gain access to the cell interior, and thus elicit a therapeutic response. Herein, evidence is provided of the use of anionic supramolecular self-associating amphiphiles (SSAs) as antimicrobial efficacy enhancers for commonly used antimicrobial agents, to which there is known resistance, against Gram-negative bacteria. The co-administration of the SSAs with antimicrobials is shown to sensitize traditionally hard to treat Pseudomonas aeruginosa to both rifampicin and novobiocin, from which structure activity relationships can be elucidated. Quantitative fluorescence microscopy is performed, indicating membrane permeabilization to be the likely mode of action of drug efficacy enhancement by the SSAs. These results offer an alternative strategy in antimicrobial adjuvant design, expanding focus beyond cationic peptides and into the realm of anionic small molecules. Finally, the self-assembly of the SSAs in the presence of these antimicrobials is investigated through a combination of quantitative NMR, tensiometry, dynamic light scattering, and zeta potential studies, demonstrating the impact of these agents on SSA self-association events.