Membrane-Targeting Poly(Amino Acids) with a Phage-Like Action Process for Antifungal Therapy.

Area of Science:

• Biochemistry
• Materials Science
• Microbiology

Background:

• Invasive fungal infections pose a significant threat, exacerbated by increasing antifungal drug resistance.
• There is an urgent need for novel antifungal strategies with unique mechanisms of action.

Purpose of the Study:

• To synthesize and evaluate a guanidine-functionalized poly(amino acid) (PArg20) as a novel antifungal agent.
• To investigate the phage-like "adsorption-penetration-disruption" mechanism of PArg20 against fungal pathogens.

Main Methods:

• Synthesis of guanidine-functionalized poly(amino acid) (PArg20).
• Characterization of PArg20's antifungal activity and mechanism of action, including membrane interaction and intracellular disruption.
• Assessment of PArg20's efficacy in murine models of fungal keratitis and systemic infection.
• Evaluation of PArg20's resistance profile through serial passages.

Main Results:

• PArg20 demonstrated superior antifungal activity compared to clinical drugs, reducing eradication time from over 2 hours to 10 minutes.
• The compound exhibited a phage-like mechanism: electrostatic adsorption, membrane penetration, and intracellular disruption (mitochondrial dysfunction, oxidative stress, nuclear rupture).
• PArg20 showed no significant resistance development after 15 passages and effectively reduced fungal burden and inflammation in vivo.

Conclusions:

• PArg20 represents a potent new antifungal agent with a unique phage-like mechanism.
• This approach offers rapid fungal eradication and circumvents common resistance pathways.
• PArg20 shows promise for combating invasive fungal infections and overcoming drug resistance.