Polycatechol-based iron predators disrupt fungal iron homeostasis to drive selective antifungal action

Area of Science:

• Polymer Chemistry
• Mycology
• Drug Discovery

Background:

• Fungal infections present a significant global health threat due to limited effective treatments and increasing drug resistance.
• Cationic polymers show promise as antifungals but suffer from nonselective membrane disruption and cytotoxicity.
• Developing novel antifungal agents with targeted mechanisms and improved safety profiles is crucial.

Purpose of the Study:

• To develop a novel class of polycatechols, termed fungal iron predators (FIPs), as targeted antifungal agents.
• To investigate the mechanism of action of FIPs, focusing on iron sequestration and metabolic disruption.
• To optimize FIPs for potent antifungal activity, low cytotoxicity, and minimal resistance development.

Main Methods:

• Synthesis and characterization of polycatechol-based fungal iron predators (FIPs).
• Evaluation of FIPs' antifungal activity against various fungal species and assessment of cytotoxicity in mammalian cells.
• Investigation of FIPs' mechanism of action, including cellular uptake, iron sequestration, and impact on mitochondrial function.
• Optimization of FIP structure (cationic density, catechol stoichiometry) for enhanced efficacy and selectivity.
• In vivo testing of lead FIP candidates in preclinical models of fungal infection.

Main Results:

• Developed FIPs exhibit potent fungicidal activity through selective iron sequestration and disruption of fungal iron homeostasis.
• FIPs induce iron starvation, leading to mitochondrial dysfunction, energy collapse, and fungal cell death.
• An optimized FIP variant demonstrated high selectivity for fungi over mammalian cells, minimal resistance induction, and antioxidant properties.
• The lead FIP candidate showed robust therapeutic efficacy in multiple in vivo models of fungal infection.
• The study established a new paradigm in antifungal polymer design, shifting from membrane disruption to targeted intracellular metabolic interference.

Conclusions:

• Fungal iron predators (FIPs) represent a novel class of antifungals with a targeted mechanism of action based on iron metabolism disruption.
• FIPs offer a promising strategy for developing next-generation antifungal agents with improved efficacy, selectivity, and reduced resistance potential.
• This approach of targeting intracellular metabolic pathways provides a versatile platform for designing precision antifungal polymers.