Discovery of novel targets for important human and plant fungal pathogens via an automated computational pipeline HitList

Abstract

Fungi are a major threat to human health and agricultural productivity, causing 1.7 million human deaths and billions of dollars in crop losses and spoilage annually. While various antifungal compounds have been developed to combat these fungi in medical and agricultural settings, there are concerns that effectiveness is waning due to the emergence of acquired drug resistance and novel pathogens. Effectiveness is further hampered due to the limited number of modes of action for available antifungal compounds. To develop new strategies for the control and mitigation of fungal disease and spoilage, new antifungals are needed with novel fungal-specific protein targets that can overcome resistance, prevent host toxicity, and can target fungi that have no effective control measures. The increasing availability of complete genomes of pathogenic and spoilage fungi has enabled identification of novel protein targets essential for viability and not found in host plants or humans. In this study, an automated bioinformatics pipeline utilizing BLAST, Clustal Ω , and subtractive genomics was created and used to identify potential new targets for any combination of hosts and pathogens with available genomic or proteomic data. This pipeline called HitList allows in silico screening of thousands of possible targets. HitList was then used to generate a list of potential antifungal targets for the World Health Organization fungal priority pathogens list and the top 10 agricultural fungal pathogens. Known antifungal targets were found, validating the approach, and an additional eight novel protein targets were discovered that could be used for the rational design of antifungal compounds.