Targeting iron acquisition mechanisms of invasive fungal infections: old and new insights

Abstract

The development of antifungal drugs encounters a significant challenge due to the close phylogenetic relationship between fungi and mammals, both being eukaryotic organisms that share many similar cellular and molecular processes. The toxicity of antifungal compounds is bilaterally distributed, complicating the development of highly selective therapeutic agents. The four classes of antifungals for treating invasive fungal infections—polyene macrolides, azoles, pyrimidine analogs, and echinocandins—offer therapeutic benefits but also have limitations regarding their spectrum of activity, route of administration, drug interactions, toxicity, limited ability to target multiple fungal sites, resistance to monotherapy, and short half-life. These limitations, alongside the emergence of antifungal-resistant strains and new multiresistant species like Candida auris, contribute to inadequate therapeutic effects and rising mortality rates. Research into the pathogenic mechanisms of potentially invasive fungi, particularly their nutritional vulnerability to iron, is driven by the need to diversify antifungal „armamentarium”, as iron is crucial for their survival and virulence in the host. The challenge of developing new antifungal drugs has shifted research toward improving existing ones. This promising approach combines conventional therapies with strategies targeting iron acquisition, potentially lowering therapeutic doses and addressing multiple targets, which could slow the development of resistance.