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Identification and modeling of a drug target for Clostridium perfringens SM101.

Chhabra G, Sharma P, Anant A, Deshmukh S, Kaushik H, Gopal K, Srivastava N, Sharma N, Garg LC - Bioinformation (2010)

Bottom Line: The study resulted in the identification of 426 such genes.The number of these potential drug targets thus identified is significantly lower than the genome's protein coding capacity (2558 protein coding genes).Our results show that there are only 5 essential genes of C. perfringens that exhibit similarity with 12 species of the 14 different bacterial species present in DEG database.

View Article: PubMed Central - PubMed

Affiliation: Gene Regulation Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi – 110067, India.

ABSTRACT
In the present study, comparative genome analysis between Clostridium perfringens and the human genome was carried out to identify genes that are essential for the pathogen's survival, and non-homologous to the genes of human host, that can be used as potential drug targets. The study resulted in the identification of 426 such genes. The number of these potential drug targets thus identified is significantly lower than the genome's protein coding capacity (2558 protein coding genes). The 426 genes of C. perfringens were further analyzed for overall similarities with the essential genes of 14 different bacterial species present in Database of Essential Genes (DEG). Our results show that there are only 5 essential genes of C. perfringens that exhibit similarity with 12 species of the 14 different bacterial species present in DEG database. Of these, 1 gene was similar in 12 species and 4 genes were similar in 11 species. Thus, the study opens a new avenue for the development of potential drugs against the highly pathogenic bacterium. Further, by selecting these essential genes of C. perfringens, which are common and essential for other pathogenic microbial species, a broad spectrum anti-microbial drug can be developed. As a case study, we have built a homology model of one of the potential drug targets, ABC transporter-ATP binding protein, which can be employed for in silico docking studies by suitable inhibitors.

No MeSH data available.


Graphical representation of the number of target genes aving similarity with those of bacterial species present in DEG. The number ofgenes of C. perfringens having similar match to different number of bacterial species is shown on top of the respective bars.
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Figure 2: Graphical representation of the number of target genes aving similarity with those of bacterial species present in DEG. The number ofgenes of C. perfringens having similar match to different number of bacterial species is shown on top of the respective bars.

Mentions: The circular genome of C. perfringens comprises 2,897,393 nucleotideswith a total number of 2701 genes. Of the 2558 protein encoding genes,only 2300 genes encode proteins of greater than 100 amino acidresidues. BLAST analysis of these genes against the human genomesequence revealed 1991 genes to be non-homologous to humans.Further BLASTP analysis of the 2300 protein coding genes with DEGresulted in identification of 726 genes, which had a bit score of at least100 at an expectation cutoff value of 10-10, as similar to the essentialgenes required for the growth and survival of bacteria listed in the DEG.Of these, 426 were found to have no human homologue (see Table 1 insupplementary data). Pathways information for these genes wasobtained from KEGG database. All these genes are involved in theproduction of proteins that are useful for various important functions inC. perfringens. Out of the 426 identified genes, function of 10 genesremains unknown, and 17 genes encode conserved hypotheticalproteins. The percentage distribution of the genes amongst differentbiological process is shown in Figure 1. A large population of thesegenes (∽33%) is involved in metabolic pathways. The major share ofthese genes constitute the proteins involved in transport and translation(17% and 12%, respectively). Highly conserved genes, in theory, aremore likely to be physiologically important [26]; however, they need tobe experimentally validated. Therefore, the analysis of the 426 essentialgenes of C. perfringens for overall similarities with all 14 speciespresent in DEG database was carried out. Results of such an analysisare shown in Figure 2. Out of the 426 essential genes, 160 genes havesimilar match to at least 1 species, whereas on the other end of thespectrum, only 4 genes have similar match to 11 species and only 1gene has an identity score of more than 100 with 12 different microbialspecies listed in the DEG. From this analysis, it is evident that theproducts of 5 genes (1 gene similar in 12 species and 4 genes similar in11 species) are essential for most of the bacterial species present inDEG. These species include Acinetobacter baylyi ADP1, Bacillussubtilis, Escherichia coli MG1655, Francisella novicida U112,Haemophilus influenzae, Helicobacter pylori 26695, Helicobacterpylori J99, Mycobacterium tuberculosis H37Rv, Mycoplasmagenitalium G37, Mycoplasma pulmonis UAB CTIP , Salmonellatyphimurium, Staphylococcus aureus and Streptococcus pneumoniae.Therefore, these 5 genes can be used as potential drug targets for morethan 10 highly pathogenic bacterial species, in addition to C.perfringens. These 5 target genes, thus identified, are ABC transporter-ATP-binding protein, cell division protein FtsZ, RNA polymerasesigma factor RpoD, 50S ribosomal protein L13, and 30S ribosomalprotein S5. A drug designed against these targets can be effectivelyused to treat other bacterial infections as well. Since the number of thusidentified potential candidate genes is relatively small, these can beexperimentally validated to develop broad-spectrum antimicrobialdrugs. Since ABC transporter-ATP-binding protein is one of the 5potential drug targets identified, an attempt has been made to predict itsstructure for effective drug design.


Identification and modeling of a drug target for Clostridium perfringens SM101.

Chhabra G, Sharma P, Anant A, Deshmukh S, Kaushik H, Gopal K, Srivastava N, Sharma N, Garg LC - Bioinformation (2010)

Graphical representation of the number of target genes aving similarity with those of bacterial species present in DEG. The number ofgenes of C. perfringens having similar match to different number of bacterial species is shown on top of the respective bars.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2957761&req=5

Figure 2: Graphical representation of the number of target genes aving similarity with those of bacterial species present in DEG. The number ofgenes of C. perfringens having similar match to different number of bacterial species is shown on top of the respective bars.
Mentions: The circular genome of C. perfringens comprises 2,897,393 nucleotideswith a total number of 2701 genes. Of the 2558 protein encoding genes,only 2300 genes encode proteins of greater than 100 amino acidresidues. BLAST analysis of these genes against the human genomesequence revealed 1991 genes to be non-homologous to humans.Further BLASTP analysis of the 2300 protein coding genes with DEGresulted in identification of 726 genes, which had a bit score of at least100 at an expectation cutoff value of 10-10, as similar to the essentialgenes required for the growth and survival of bacteria listed in the DEG.Of these, 426 were found to have no human homologue (see Table 1 insupplementary data). Pathways information for these genes wasobtained from KEGG database. All these genes are involved in theproduction of proteins that are useful for various important functions inC. perfringens. Out of the 426 identified genes, function of 10 genesremains unknown, and 17 genes encode conserved hypotheticalproteins. The percentage distribution of the genes amongst differentbiological process is shown in Figure 1. A large population of thesegenes (∽33%) is involved in metabolic pathways. The major share ofthese genes constitute the proteins involved in transport and translation(17% and 12%, respectively). Highly conserved genes, in theory, aremore likely to be physiologically important [26]; however, they need tobe experimentally validated. Therefore, the analysis of the 426 essentialgenes of C. perfringens for overall similarities with all 14 speciespresent in DEG database was carried out. Results of such an analysisare shown in Figure 2. Out of the 426 essential genes, 160 genes havesimilar match to at least 1 species, whereas on the other end of thespectrum, only 4 genes have similar match to 11 species and only 1gene has an identity score of more than 100 with 12 different microbialspecies listed in the DEG. From this analysis, it is evident that theproducts of 5 genes (1 gene similar in 12 species and 4 genes similar in11 species) are essential for most of the bacterial species present inDEG. These species include Acinetobacter baylyi ADP1, Bacillussubtilis, Escherichia coli MG1655, Francisella novicida U112,Haemophilus influenzae, Helicobacter pylori 26695, Helicobacterpylori J99, Mycobacterium tuberculosis H37Rv, Mycoplasmagenitalium G37, Mycoplasma pulmonis UAB CTIP , Salmonellatyphimurium, Staphylococcus aureus and Streptococcus pneumoniae.Therefore, these 5 genes can be used as potential drug targets for morethan 10 highly pathogenic bacterial species, in addition to C.perfringens. These 5 target genes, thus identified, are ABC transporter-ATP-binding protein, cell division protein FtsZ, RNA polymerasesigma factor RpoD, 50S ribosomal protein L13, and 30S ribosomalprotein S5. A drug designed against these targets can be effectivelyused to treat other bacterial infections as well. Since the number of thusidentified potential candidate genes is relatively small, these can beexperimentally validated to develop broad-spectrum antimicrobialdrugs. Since ABC transporter-ATP-binding protein is one of the 5potential drug targets identified, an attempt has been made to predict itsstructure for effective drug design.

Bottom Line: The study resulted in the identification of 426 such genes.The number of these potential drug targets thus identified is significantly lower than the genome's protein coding capacity (2558 protein coding genes).Our results show that there are only 5 essential genes of C. perfringens that exhibit similarity with 12 species of the 14 different bacterial species present in DEG database.

View Article: PubMed Central - PubMed

Affiliation: Gene Regulation Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi – 110067, India.

ABSTRACT
In the present study, comparative genome analysis between Clostridium perfringens and the human genome was carried out to identify genes that are essential for the pathogen's survival, and non-homologous to the genes of human host, that can be used as potential drug targets. The study resulted in the identification of 426 such genes. The number of these potential drug targets thus identified is significantly lower than the genome's protein coding capacity (2558 protein coding genes). The 426 genes of C. perfringens were further analyzed for overall similarities with the essential genes of 14 different bacterial species present in Database of Essential Genes (DEG). Our results show that there are only 5 essential genes of C. perfringens that exhibit similarity with 12 species of the 14 different bacterial species present in DEG database. Of these, 1 gene was similar in 12 species and 4 genes were similar in 11 species. Thus, the study opens a new avenue for the development of potential drugs against the highly pathogenic bacterium. Further, by selecting these essential genes of C. perfringens, which are common and essential for other pathogenic microbial species, a broad spectrum anti-microbial drug can be developed. As a case study, we have built a homology model of one of the potential drug targets, ABC transporter-ATP binding protein, which can be employed for in silico docking studies by suitable inhibitors.

No MeSH data available.