Subtractive Genomics Approach for in Silico Identification and Characterization of Novel Drug Targets in Neisseria Meningitides Serogroup B

Aditya Narayan Sarangi

doi:10.4172/jcsb.1000038

Abstract

Meningococcal disease is a life-threatening illness with annual incidence rates varying from 1 to 1000 per 100 000 persons in different parts of the world. Effective polysaccharide and polysaccharide-protein conjugate vaccines that offer protection against infection with meningococcal serogroups A, C, Y and W-135 have been licensed and are available worldwide. Serogroup B remains the most prevalent cause of meningococcal disease responsible for 32% of all meningococcal disease in the United States, 45 to 80% of the cases in Europe, and for the majority of cases in the rest of the world. The development of a vaccine against serogroup B poses the biggest problem due to the similarity between the B capsular polysaccharide structure and a polysialic acid containing glycopeptides that are a part of human brain tissue. Prevention of meningococcal disease will require the development of an effective vaccine to combat serogroup B, which is the cause of most meningococcal cases in developed countries. The availability of the complete sequence information of Neisseria meningitides serogroup B proteome has made it possible to carry out the in silico analysis of its genome for identification of potential vaccine and drug targets. Our study revealed 1413 proteins which are non-homologous to human genome. Screening these proteins using the Database of Essential Genes (DEG) resulted in the identification of 362 proteins as essential proteins of the bacterium. Analysis of the identified essential proteins, using the KEGG Automated Annotation Server (KAAS) housed at Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways database, revealed 35 enzymes of N. Meningitides that may be used as potential drug targets, as they belongs to pathways present only in the bacterium and not present in humans. Subcelluler localization prediction of these essential proteins revealed that 9 proteins lie on the outer membrane of the pathogen which could be potential vaccine targets. Screening of the functional inhibitors against these novel targets may result in discovery of novel therapeutic compounds that can be effective against Neisseria meningitides Serogroup B.

Highlights

Despite rapid advances in the diagnosis of bacterial infections and the availability of effective antibiotics, meningococcal disease continues to represent a substantial public health problem for most countries (Tzeng et al, 2000)
All the proteins of N. meningitides that are non-homologous to the human proteome could not be taken directly as targets as these include a large number of proteins which are not essential for the viability of the organism
Out of 1939 proteins, 1413 proteins were identified as non-homologues to the human proteome and were subjected to BLASTP against Database of Essential Genes (DEG) with expectation value (E-value) cutoff score of [10] and 30% identity. 362 proteins comprising 18% of the total number of protein coding sequences in N. meningitides serogroup B found to be essential

Summary

Introduction

Despite rapid advances in the diagnosis of bacterial infections and the availability of effective antibiotics, meningococcal disease continues to represent a substantial public health problem for most countries (Tzeng et al, 2000). The bacterium can traverse the epithelium and reach the blood stream causing septicemia. From the blood meningococcus is able to cross the blood brain barrier and infect the meninges, causing meningitis potentially leading to shock and death (van et al, 2000; Stephens et al, 2007). 95% of total cases of meningitis are caused by five major serogroups: A, B, C, Y and W135. Vaccines against serogroups A, C, Y and W135 were developed in the 1960s by using the purified capsular polysaccharide as antigen. In the last 40 years a lot of efforts have been directed to the identification of meningococcus B antigens as basis of new vaccines. The high variability of these proteins among the different MenB strains represents a serious obstacle to the production of a globally effective anti-MenB vaccine (Stephens et al, 2007)

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Conclusion