The intricate link between iron, mitochondria and azoles in Candida species

Invasive fungal infections are rapidly increasing, and the opportunistic pathogenic Candida species are the fourth most common cause of nosocomial systemic infections. The current antifungal classes, of which azoles are the most widely used, all have shortcomings. Azoles are generally considered fungistatic rather than fungicidal, they do not actively kill fungal cells and therefore resistance against azoles can be rapidly acquired. Combination therapies with azoles provide an interesting therapeutic outlook and agents limiting iron are excellent candidates. We summarize how iron is acquired by the host and transported towards both storage and iron-utilizing organelles. We indicate whether these pathways alter azole susceptibility and/or tolerance, to finally link these transport mechanisms to mitochondrial iron availability. In this review, we highlight putative novel intracellular iron shuffling mechanisms and indicate that mitochondrial iron dynamics in relation to azole treatment and iron limitation is a significant knowledge gap.

Automated summary

Invasive fungal infections, particularly caused by Candida species, are on the rise and pose a significant challenge in healthcare settings. The current antifungal drugs, especially azoles, have limitations including fungistatic activity and the rapid development of resistance. Combination therapies involving azoles and agents that limit iron availability show promising prospects. This review summarizes the mechanisms of iron acquisition, transport, and storage in host cells, and discusses how these pathways may affect azole susceptibility and tolerance. Furthermore, it emphasizes the importance of understanding mitochondrial iron dynamics in relation to azole treatment and iron limitation, which remains a significant gap in knowledge.