Analysis of the Protein Domain and Domain Architecture Content in Fungi and Its Application in the Search of New Antifungal Targets

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.

The Mechanistic Targets of Antifungal Agents: An Overview

“…More recently, with the advent of the AIDS epidemic, the increasing number of patients living with suppressed immune systems and the lack of effective drugs for the treatment of systemic fungal infections, there has been resurgence in the interest in the development of new antifungal agents [12, 13]. Other conditions such as the increased frequency of bone marrow and organ transplants, prolonged use of corticosteroids, the use of antineoplastic agents, abusive use of antibiotics [14] and the emergence of fungal resistance to currently available agents have made the need for new and effective antifungal agents a high priority [15–18].…”

Classification of proteins with shared motifs and internal repeats in the ECOD database

“…The events which lead to domain shuffling, such as terminal deletion, gene fusion, and fission, have been studied extensively on sequence databases and across whole genomes . Many studies have examined the frequency of domain shuffling both across domains of life, fully sequenced genomes, and in the host‐pathogen context of comparative genomics . The biological mechanisms that lead to small repeat deletion/extensions are distinct from those that lead to larger scale domain shuffling .…”

New pathogens, new tricks: emerging, drug‐resistant fungal pathogens and future prospects for antifungal therapeutics

“…), and the protein phosphatase calcineurin . Antifungal drug target identification has also benefited from computational methods used to compare human and fungal proteomes, in order to identify fungal‐specific domains with potential to bind small molecules . These avenues lay the groundwork for future antifungal drug development pipelines.…”

“…236,[239][240][241] Antifungal drug target identification has also benefited from computational methods used to compare human and fungal proteomes, in order to identify fungal-specific domains with potential to bind small molecules. 242 These avenues lay the groundwork for future antifungal drug development pipelines. Garvey et al, 220 Ong et al, 223 Pfaller et al 225 High rates of acquired resistance to fluconazole, voriconazole, and echinocandins New antifungal APX001 targeting GPI synthesis…”