Supramolecular high-aspect ratio assemblies with strong antifungal activity

Area of Science:

• Medicinal Chemistry
• Materials Science
• Antimicrobial Research

Background:

• Drug resistance in fungal pathogens necessitates novel antifungal agents.
• Current treatments often exhibit significant host toxicity and limited specificity.
• Cationic polymers have shown promise but lack precise molecular control.

Purpose of the Study:

• To develop and characterize novel cationic small molecules with potent antifungal activity.
• To investigate the self-assembly properties and nanostructure formation of these molecules.
• To evaluate the efficacy and safety of these compounds against drug-resistant fungal strains.

Main Methods:

• Synthesis and characterization of terephthalamide-bisurea based cationic small molecules.
• Computational modeling to predict molecular arrangements and self-assembly behavior.
• Transmission electron microscopy (TEM) and atomic force microscopy (AFM) for nanostructure analysis.
• In vitro and in vivo antifungal assays against sensitive and resistant fungal strains.
• Biocompatibility testing and assessment of drug resistance induction.

Main Results:

• Cationic small molecules demonstrated pathogen-specific antifungal activity with high microbial selectivity and low host toxicity.
• Spontaneous supramolecular self-assembly resulted in polymer-like nanostructures confirmed by microscopy.
• Effective antifungal action against both drug-sensitive and drug-resistant fungal strains was observed.
• In vitro and in vivo biocompatibility was confirmed, with no significant toxicity observed in a mouse keratitis model.
• No induction of fungal drug resistance was observed even after repeated sub-lethal exposures.

Conclusions:

• Terephthalamide-bisurea based cationic small molecules represent a novel class of effective antifungal agents.
• Their ability to self-assemble into nanostructures contributes to their potent antimicrobial activity.
• These compounds offer a promising alternative to existing antifungals due to their specificity, low toxicity, and lack of resistance induction.