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

Abstract

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.

Advancements in antimicrobial nanoscale materials and self-assembling systems

“…Hiscock and co-workers also investigated their SSA compounds as enhancers of antimicrobial agents towards E. coli (DH10β) and P. aeruginosa (PAO1). 239,240 In these studies, one such SSA displayed enhanced efficacy of cisplatin, ampicillin and octenidine, whilst several other SSAs enhanced the efficacy of novobiocin and rifampicin, confirming SSAs can also increase the activity of other drugs to achieve antimicrobial activity. Thus, the SSAs represent a new class of multifunctional antibacterial materials.…”

Tools to enable the study and translation of supramolecular amphiphiles

“…The change in chemical shift values are then fitted to a binding isotherm model that allows for elucidation of any corresponding selfassociative binding constants. 36,37,41 The two most widely utilised single self-associative binding models applicable here are the co-operative equal K (CoEK) model, which assumes the first association event is different from all subsequent identical association events, 42 and the dimerisation/equal K (EK) model, where all association events are equal. Here both models assume one component, unidirectional homogenous aggregation events.…”

Controlling the structure of supramolecular fibre formation for benzothiazole based hydrogels with antimicrobial activity against methicillin resistantStaphylococcus aureus

“…The hypothesised mode of action for these SSAs include selective membrane coordination and disruption. 23 Furthermore, SSAs have been shown to: (i) act as (potential) drug delivery systems; 24,25 (ii) enhance the activity of commonly used antimicrobials including; novobiocin and rifampicin against a variety of bacteria such as the ESKAPE pathogen, Pseudomonas aeruginosa; 26,27 (iii) enhance the activity of cisplatin against ovarian cancer cells; 28 and (iv) exhibit a druggable profile when administered intravenously to mice. 23 In general, the anionic portion of an SSA is known to selfassociate, through the formation of (thio)urea-anion intermolecular hydrogen bonds, to form anionic dimers in the solid state (Fig.…”

“…Furthermore, SSAs have been shown to: (i) act as (potential) drug delivery systems; 24,25 (ii) enhance the activity of commonly used antimicrobials including; novobiocin and rifampicin against a variety of bacteria such as the ESKAPE pathogen, Pseudomonas aeruginosa ; 26,27 (iii) enhance the activity of cisplatin against ovarian cancer cells; 28 and (iv) exhibit a druggable profile when administered intravenously to mice. 23…”