1887

Abstract

Redox pathways play a key role in pathogenesis. Glutathione, a central molecule in redox homeostasis in yeasts, is an essential metabolite, but its requirements can be met either from endogenous biosynthesis or from the extracellular milieu. In this report we have examined the importance of glutathione biosynthesis in two major human opportunistic fungal pathogens, and . As the genome sequence of had suggested the absence of glutathione transporters, we initially investigated exogenous glutathione utilization in by disruption of the gene, involved in methionine biosynthesis. We observed an organic sulphur auxotrophy in a Δ strain; however, unlike its counterpart, the Δ strain was unable to grow on exogenous glutathione. This inability to grow on exogenous glutathione was demonstrated to be due to the lack of a functional glutathione transporter, despite the presence of a functional glutathione degradation machinery (the Dug pathway). In the absence of the ability to obtain glutathione from the extracellular medium, we examined and could demonstrate that -glutamyl cysteine synthase, the first enzyme of glutathione biosynthesis, was essential in . Further, although -glutamyl cysteine synthase has been reported to be non-essential in , we report here for what is believed to be the first time that the enzyme is required for survival in human macrophages , as well as for virulence in a murine model of disseminated candidiasis. The essentiality of -glutamyl cysteine synthase in , and its essentiality for virulence in , make the enzyme a strong candidate for antifungal development.

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2011-02-01
2020-08-04
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