Abstract
Over the past several years fungal infections have shown an increasing incidence in the susceptible population, and caused high mortality rates. In parallel, multi-resistant fungi are emerging in human infections. Therefore, the identification of new potential antifungal targets is a priority. The first task of this study was to analyse the protein domain and domain architecture content of the 137 fungal proteomes (corresponding to 111 species) available in UniProtKB (UniProt KnowledgeBase) by January 2013. The resulting list of core and exclusive domain and domain architectures is provided in this paper. It delineates the different levels of fungal taxonomic classification: phylum, subphylum, order, genus and species. The analysis highlighted Aspergillus as the most diverse genus in terms of exclusive domain content. In addition, we also investigated which domains could be considered promiscuous in the different organisms. As an application of this analysis, we explored three different ways to detect potential targets for antifungal drugs. First, we compared the domain and domain architecture content of the human and fungal proteomes, and identified those domains and domain architectures only present in fungi. Secondly, we looked for information regarding fungal pathways in public repositories, where proteins containing promiscuous domains could be involved. Three pathways were identified as a result: lovastatin biosynthesis, xylan degradation and biosynthesis of siroheme. Finally, we classified a subset of the studied fungi in five groups depending on their occurrence in clinical samples. We then looked for exclusive domains in the groups that were more relevant clinically and determined which of them had the potential to bind small molecules. Overall, this study provides a comprehensive analysis of the available fungal proteomes and shows three approaches that can be used as a first step in the detection of new antifungal targets.
Highlights
There has been a significant rise in the incidence of fungal infection over the last few years
The biological goal of this study was to analyse the functional implications of protein domains and domain combinations in the available fungal proteomes
This information can be used to highlight proteins and pathways that could be potentially used as drug targets
Summary
There has been a significant rise in the incidence of fungal infection over the last few years. This has been partially due to an increase in the susceptible population as the result of blood cancer, intensive care, solid organ transplantation, or chronic granulomatous disease, in addition to a growing number of patients receiving high doses of corticosteroids or other immunosuppressive treatments [1,2]. IFI constitutes even a more important problem for immunocompromised patients, with mortality reaching up to 90% [6]. The success of available antifungal therapies is limited by the drug toxicity for the host (resulting potentially in severe side effects) and the late detection and treatment of the infection [7]. The discovery of new drug targets and antifungal drugs with a broader spectrum of activity is one active field of research
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