Microbial Metabolite Inspired β-Peptide Polymers Displaying Potent and Selective Antifungal Activity

Area of Science:

• Biochemistry
• Microbiology
• Materials Science

Background:

• Rising incidence of invasive fungal infections necessitates novel antifungal agents.
• Limited efficacy and increasing resistance to current antifungal drugs pose significant challenges.
• Microbial metabolites serve as a valuable source for discovering new antimicrobial compounds.

Purpose of the Study:

• To design and synthesize potent and selective antifungal agents, poly(DL-diaminopropionic acid) (PDAP).
• To investigate the mechanism of action of PDAP against fungal cells.
• To evaluate the efficacy and safety of PDAP in preclinical models.

Main Methods:

• Ring-opening polymerization of β-amino acid N-thiocarboxyanhydrides to produce PDAP.
• Assessment of antifungal activity using minimum inhibitory concentration (MIC) assays.
• Evaluation of cytotoxicity, hemolysis, and biofilm inhibition.
• In vivo studies using a fungal keratitis model.

Main Results:

• Optimal PDAP demonstrated potent antifungal activity against Candida albicans (MIC = 0.4 µg mL⁻¹).
• PDAP exhibited negligible hemolysis and cytotoxicity, and was effective against antifungal-resistant strains.
• PDAP inhibited fungal biofilm formation and eradicated mature biofilms.
• In vivo studies confirmed PDAP's safety and efficacy in treating fungal keratitis.

Conclusions:

• PDAP is a potent and selective antifungal agent with a novel mechanism of action.
• PDAP overcomes existing antifungal resistance mechanisms.
• PDAP shows promise as a safe and effective therapeutic agent for invasive fungal infections and fungal keratitis.