Iron-sulphur cluster biogenesis: deciphering new molecular mechanisms and exploiting novel antifungal and fungicide targets

Descripción del proyecto

Hacia nuevos tratamientos antimicóticos

Las infecciones micóticas provocan millones de muertes cada año, aunque los hongos también pueden causar daños en plantas y cosechas, lo cual provoca pérdidas significativas en la producción de alimentos. A pesar de que hay fármacos antimicóticos y fungicidas disponibles, la aparición de farmacorresistencia subraya la necesidad de desarrollar nuevos fármacos. El objetivo del proyecto financiado con fondos europeos FungiFeS es la identificación de compuestos naturales que puedan servir como nuevos antimicóticos o fungicidas. Los investigadores proponen como nuevas dianas los grupos hierro–azufre (FeS) que se encuentran en las proteínas que intervienen en procesos como la respiración celular. Los resultados generarán nuevas terapias combinatorias antimicóticas que podrían mejorar la salud humana y la disponibilidad de alimentos en todo el mundo.

Objetivo

Fungi have major socioeconomic impacts. Recent estimates suggest that invasive human fungal infections kill more than 1.6 million people annually and that 600 million people could be fed each year by halting the spread of fungal diseases in the five most important crops. A range of antifungals/fungicides is currently used to control fungal pathogens in medicine and agriculture, but resistance to those is growing underscoring the urgent need for new molecular targets and treatments. Iron-sulphur (FeS) clusters are inorganic cofactors found in all kingdoms of life and required for several essential cellular processes, such as DNA synthesis, mRNA translation, and respiration. Pathways required for their biogenesis were suggested to represent possible novel antifungal/fungicide targets. The aims of the project are: (1) to identify, via chemical high throughput screening, natural compounds targeting the essential mitochondrial (Arh1-Yah1) and cytoplasmic (Tah18-Dre2) NADPH-dependant electron transfer chains involved in the FeS cluster biogenesis. These compounds could be used in combination with other agents to kill fungal pathogens lowering cost and potential toxicity by reducing doses needed to inhibit fungal growth. (2) To highlight new targets for antifungals/fungicides among the FeS cluster biogenesis and associated pathways. (3) To establish the interaction network of the ferredoxin Yah1 involved in the early steps of the FeS cluster biogenesis knowing that several steps of this process remain poorly understood and new factors may still be discovered. The project will be carried out in the group “Oxidative stress, FeS protein and Cancer” (CNRS-ICSN, Gif-sur-Yvette, France) and will address those objectives by combining my own expertise and that of the host laboratory in microbiology, genetics, biophysics and biochemistry, drug screening and of cutting-edge technologies and approaches such as Förster resonance energy transfer, microfluidics and chemoproteomics.