Supramolecular high-aspect ratio assemblies with strong antifungal activity

Abstract

Efficient and pathogen-specific antifungal agents are required to mitigate drug resistance problems. Here we present cationic small molecules that exhibit excellent microbial selectivity with minimal host toxicity. Unlike typical cationic polymers possessing molecular weight distributions, these compounds have an absolute molecular weight aiding in isolation and characterization. However, their specific molecular recognition motif (terephthalamidebisurea) facilitates spontaneous supramolecular self-assembly manifesting in several polymer-like properties. Computational modelling of the terephthalamide-bisurea structures predicts zig-zag or bent arrangements where distal benzyl urea groups stabilize the highaspect ratio aqueous supramolecular assemblies. These nanostructures are confirmed by transmission electron microscopy and atomic force microscopy. Antifungal activity against drug-sensitive and drug-resistant strains with in vitro and in vivo biocompatibility is observed. Additionally, despite repeated sub-lethal exposures, drug resistance is not induced. Comparison with clinically used amphotericin B shows similar antifungal behaviour without any significant toxicity in a C. albicans biofilm-induced mouse keratitis model.

Poly(trimethylene carbonate)-based polymers engineered for biodegradable functional biomaterials

“…In particular, the supramolecular approach raised the importance of the shape of antimicrobials upon the efficacy against some fungi. 219,221 According to a recent study by Stupp et al, the cytotoxicity of cationic supramolecular aggregates depends on the strength of the interaction in the internal domain. 222 The strong "internal binding affinity" maintains the stable cationic supramolecular structure that could rip out the cell membrane, while the weak affinity augments the dynamic nature of the cationic aggregates to release unimers by stronger interaction with cell membranes.…”

Toward hemocompatible self-assembling antimicrobial nanofibers: understanding the synergistic effect of supramolecular structure and PEGylation on hemocompatibility

“…Recently, several cationic synthetic polymers and peptides have been designed and used as the molecular building blocks to form supramolecular assemblies with tunable, nanostructure-dependent antimicrobial activity. 12, 15, 18, 21, 22 …”

Supramolecular Germicide Switches through Host‐Guest Interactions for Decelerating Emergence of Drug‐Resistant Pathogens

“…In this work, four kinds of commercial germicides with different molecular structure and counterions are selected as representatives, including dodecyl dimethyl benzyl ammonium bromide (DDBAB), dodecyl dimethyl benzyl ammonium chloride, (DDBAC), benzyl‐dimethyl‐hexadecylammonium‐chloride (BCDAC) and dodecyl trimethyl ammonium chloride (DDTMA). These germicides with quaternary ammonium (QA) groups have been widely used for clinical therapy, sewage management, crude oil transportation, etc,, and have proved to be broad‐spectrum antimicrobials against bacteria, fungi, and viruses . CB[7] as a kind of important macrocyclic molecules with excellent biocompatibility has been widely used in supramolecular systems ,.…”

“…Combining 1 H NMR data and ITC results, it is safe to say that the expected germicide switch complexes (Figure ) were constructed accurately. The bactericides bearing quaternary ammonium (QA) could efficiently kill pathogens through electrostatic and hydrophobic interactions with pathogen membrane ,,. It is expected that cationic germicide has different interaction modes with pathogens after the encapsulation of QA groups and hydrophobic groups by CB[7].…”