An integrated structural proteomics approach along the druggable genome of Corynebacterium pseudotuberculosis species for putative druggable targets. (December 2015)

• Record Type: Journal Article
• Authors: Radusky, Leandro; Hassan, Syed; Lanzarotti, Esteban; Tiwari, Sandeep; Jamal, Syed; Ali, Javed; Ali, Amjad; Ferreira, Rafaela; Barh, Debmalya; Silva, Artur; Turjanski, Adrián; Azevedo, Vasco
• Is Part Of: BMC genomics. Volume 16:Number 5(2015)
• Page Start: 1
• Page End: 8
• Publication Date: 2015-12
• Subjects: Corynebacterium pseudotuberculosis (Cp) -- Druggable genome -- Structural proteomics approach -- Putative globally/conserved druggable/bindable targets -- Caseous lymphadenitis; Genomes -- Periodicals; Gene mapping -- Periodicals; Genomics -- Periodicals; Base Sequence -- Periodicals; Chromosome Mapping -- Periodicals; Genetic Techniques -- Periodicals; Sequence Analysis, DNA -- Periodicals; 572.8605
• DOI: 10.1186/1471-2164-16-S5-S9
• Languages: English
• ISSNs: 1471-2164

Abstract

Abstract Background The bacteriumCorynebacterium pseudotuberculosis (Cp) causes caseous lymphadenitis (CLA), mastitis, ulcerative lymphangitis, and oedema in a number of hosts, comprising ruminants, thereby intimidating economic and dairy industries worldwide. So far there is no effective drug or vaccine available against Cp. Previously, a pan-genomic analysis was performed for both biovarequi and biovarovis and a Pathogenicity Islands (PAIS) analysis within the strains highlighted a large set of proteins that could be relevant therapeutic targets for controlling the onset of CLA. In the present work, a structural druggability analysis pipeline was accomplished along 15 previously sequenced Cp strains from both biovarequi and biovarovis . Methods and results We computed the whole modelome of a reference strain Cp1002 (NCBI Accession: NC_017300.1) and then the homology models of proteins, of 14 different Cp strains, with high identity (≥ 85%) to the reference strain were also done. Druggability score of all proteins pockets was calculated and only those targets that have a highly druggable (HD) pocket in all strains were kept, a set of 58 proteins. Finally, this information was merged with the previous PAIS analysis giving two possible highly relevant targets to conduct drug discovery projects. Also, off-targeting information against host organisms, includingHomo sapiens and a further analysis for protein essentiality provided a final set of 31 druggable, essential and non-host homologous targets, tabulated intable S4, additional file 1. Out of 31 globally druggable targets, 9 targets have already been reported in other pathogenic microorganisms, 3 of them (3-isopropylmalate dehydratase small subunit, 50S ribosomal protein L30, Chromosomal replication initiator protein DnaA) inC. pseudotuberculosis . Conclusion Overall we provide valuable information of possible targets againstC. pseudotuberculosis where some of these targets have already been reported in other microorganisms for drug discovery projects, also discarding targets that might be physiologically relevant but are not amenable for drug binding. We propose that the constructedin silico dataset might serve as a guidance for the scientific community to have a better understanding while selecting putative therapeutic protein candidates as druggable ones as effective measures againstC. pseudotuberculosis .