Abstract
BackgroundWolbachia (wBm) is an obligate endosymbiotic bacterium of Brugia malayi, a parasitic filarial nematode of humans and one of the causative agents of lymphatic filariasis. There is a pressing need for new drugs against filarial parasites, such as B. malayi. As wBm is required for B. malayi development and fertility, targeting wBm is a promising approach. However, the lifecycle of neither B. malayi nor wBm can be maintained in vitro. To facilitate selection of potential drug targets we computationally ranked the wBm genome based on confidence that a particular gene is essential for the survival of the bacterium.ResultswBm protein sequences were aligned using BLAST to the Database of Essential Genes (DEG) version 5.2, a collection of 5,260 experimentally identified essential genes in 15 bacterial strains. A confidence score, the Multiple Hit Score (MHS), was developed to predict each wBm gene's essentiality based on the top alignments to essential genes in each bacterial strain. This method was validated using a jackknife methodology to test the ability to recover known essential genes in a control genome. A second estimation of essentiality, the Gene Conservation Score (GCS), was calculated on the basis of phyletic conservation of genes across Wolbachia's parent order Rickettsiales. Clusters of orthologous genes were predicted within the 27 currently available complete genomes. Druggability of wBm proteins was predicted by alignment to a database of protein targets of known compounds.ConclusionRanking wBm genes by either MHS or GCS predicts and prioritizes potentially essential genes. Comparison of the MHS to GCS produces quadrants representing four types of predictions: those with high confidence of essentiality by both methods (245 genes), those highly conserved across Rickettsiales (299 genes), those similar to distant essential genes (8 genes), and those with low confidence of essentiality (253 genes). These data facilitate selection of wBm genes for entry into drug design pipelines.
Highlights
Wolbachia is an obligate endosymbiotic bacterium of Brugia malayi, a parasitic filarial nematode of humans and one of the causative agents of lymphatic filariasis
In order to computationally predict essential genes, we used BLAST to compare the protein sequences of all protein-coding wBm genes to the genes contained within Database of Essential Genes (DEG)
Because DEG consists of information on essential genes in multiple bacterial organisms, we wished to evaluate the BLAST results in a manner which accounts for the statistical significance of hits to multiple DEG organisms
Summary
Wolbachia (wBm) is an obligate endosymbiotic bacterium of Brugia malayi, a parasitic filarial nematode of humans and one of the causative agents of lymphatic filariasis. Exponential growth in the amount of available genomic information has produced unprecedented opportunities to computationally predict functional genomics in biologically intractable organisms. One application of these data is facilitation of the rational drug design process. Rational drug design, seeks to utilize genomic information to identify and inhibit targets. Often these methods utilize in silico sequence analysis to choose a target protein that is important to the survival of the organism and accessible to small molecule drugs. It has been suggested that ideally a target should fulfill four properties: 1--Essentiality to the survival or pathogenesis of the target organism, 2--Druggability, having protein structure characteristics making it amenable to binding small molecule inhibitors, 3--Functional and structural characterization with established assays for screening small molecule inhibition, 4--Distinctness from current drug targets to avoid resistance [1]
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