Proteome scale comparative modeling for conserved drug and vaccine targets identification in Corynebacterium pseudotuberculosis

Syed Shah Hassan,Antaripa Bhattacharya,Neha Jain,Arshad Islam,Debmalya Barh,Neha Barve Sharma,Luís Carlos Guimarães,Lucky Juneja,Síntia Almeida,Vasco Azevedo,Siomar De Castro Soares,Syed Babar Jamal,Anderson Miyoshi,Amjad Ali,Rafaela Salgado Ferreira,Sandeep Tiwari,Fabiana Dias Póvoa,Edson Luiz Folador ,Adrián Turjanski ,Artur M S Silva ,Vinícius Augusto Carvalho De Abreu

doi:10.1186/1471-2164-15-s7-s3

Abstract

Corynebacterium pseudotuberculosis (Cp) is a pathogenic bacterium that causes caseous lymphadenitis (CLA), ulcerative lymphangitis, mastitis, and edematous to a broad spectrum of hosts, including ruminants, thereby threatening economic and dairy industries worldwide. Currently there is no effective drug or vaccine available against Cp. To identify new targets, we adopted a novel integrative strategy, which began with the prediction of the modelome (tridimensional protein structures for the proteome of an organism, generated through comparative modeling) for 15 previously sequenced C. pseudotuberculosis strains. This pan-modelomics approach identified a set of 331 conserved proteins having 95-100% intra-species sequence similarity. Next, we combined subtractive proteomics and modelomics to reveal a set of 10 Cp proteins, which may be essential for the bacteria. Of these, 4 proteins (tcsR, mtrA, nrdI, and ispH) were essential and non-host homologs (considering man, horse, cow and sheep as hosts) and satisfied all criteria of being putative targets. Additionally, we subjected these 4 proteins to virtual screening of a drug-like compound library. In all cases, molecules predicted to form favorable interactions and which showed high complementarity to the target were found among the top ranking compounds. The remaining 6 essential proteins (adk, gapA, glyA, fumC, gnd, and aspA) have homologs in the host proteomes. Their active site cavities were compared to the respective cavities in host proteins. We propose that some of these proteins can be selectively targeted using structure-based drug design approaches (SBDD). Our results facilitate the selection of C. pseudotuberculosis putative proteins for developing broad-spectrum novel drugs and vaccines. A few of the targets identified here have been validated in other microorganisms, suggesting that our modelome strategy is effective and can also be applicable to other pathogens.

Highlights

Antimicrobial resistance involving a rapid loss of effectiveness in antibiotic treatment and the increasing number of multi-resistant microbial strains pose global challenges and threats
Corynebacterium pseudotuberculosis (Cp) is a pathogen of great veterinary and economic importance, since it affects animal livestock, mainly sheep and goats, worldwide, and its presence is reported in other mammals in several Arabic, Asiatic, East and West African and North and South American countries, as well as in Australia [1]
A recent study showed that phylogenetic analysis for the identification of Corynebacterium and other CMNR species based on rpoB gene sequences are more accurate than analyses based on 16S rRNA [4]

Summary

Introduction

Antimicrobial resistance involving a rapid loss of effectiveness in antibiotic treatment and the increasing number of multi-resistant microbial strains pose global challenges and threats. Corynebacterium pseudotuberculosis (Cp) is a pathogen of great veterinary and economic importance, since it affects animal livestock, mainly sheep and goats, worldwide, and its presence is reported in other mammals in several Arabic, Asiatic, East and West African and North and South American countries, as well as in Australia [1]. Based on rpoB gene (a β subunit of RNA polymerase), it shows a close phylogenetic relationship with other type strains of CMNR (Corynebacterium, Mycobacterium, Nocardia and Rhodococcus), a group that comprises genera of great medical, veterinary and biotechnological importance [1, 3]. A recent study showed that phylogenetic analysis for the identification of Corynebacterium and other CMNR species based on rpoB gene sequences are more accurate than analyses based on 16S rRNA [4]. Given the medical importance of Cp and a lack of efficient medicines, in this study we applied a computational strategy to search for new molecular targets from this bacterium

Methods

Results

Conclusion