In-silico Subtractive Proteomic Analysis Approach for Therapeutic Targets in MDR Salmonella enterica subsp. enterica serovar Typhi str. CT18

Author(s): Noor Rahman, Ijaz Muhammad, Gul E. Nayab, Haroon Khan*, Rosanna Filosa, Jianbo Xiao, Sherif T.S. Hassan

Journal Name: Current Topics in Medicinal Chemistry

Volume 19 , Issue 29 , 2019

DOI : 10.2174/1568026619666191105102156

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Abstract:

Objective: In the present study, an attempt has been made for subtractive proteomic analysis approach for novel drug targets in Salmonella enterica subsp. enterica serover Typhi str.CT18 using computational tools.

Methods: Paralogous, redundant and less than 100 amino acid protein sequences were removed by using CD-HIT. Further detection of bacterial proteins which are non-homologous to host and are essential for the survival of pathogens by using BLASTp against host proteome and DEG`s, respectively. Comparative Metabolic pathways analysis was performed to find unique and common metabolic pathways. The non-redundant, non-homologous and essential proteins were BLAST against approved drug targets for drug targets while Psortb and CELLO were used to predict subcellular localization.

Results: There were 4473 protein sequences present in NCBI Database for Salmonella enterica subsp. enterica serover Typhi str. CT18 out of these 327 were essential proteins which were non-homologous to human. Among these essential proteins, 124 proteins were involved in 19 unique metabolic pathways. These proteins were further BLAST against approved drug targets in which 7 cytoplasmic proteins showed druggability and can be used as a therapeutic target.

Conclusion: Drug targets identification is the prime step towards drug discovery. We identified 7 cytoplasmic druggable proteins which are essential for the pathogen survival and non-homologous to human proteome. Further in vitro and in vivo validation is needed for the evaluation of these targets to combat against salmonellosis.

Keywords: Salmonellosis, Therapeutic target, Multi-drug-resistance, Database of essential genes, Druggability, Proteomic.

[1]
Everest, P.; Wain, J.; Roberts, M.; Rook, G.; Dougan, G. The molecular mechanisms of severe typhoid fever. Trends Microbiol., 2001, 9(7), 316-320.
[http://dx.doi.org/10.1016/S0966-842X(01)02067-4] [PMID: 11435104]
[2]
Galán, J.E. Molecular genetic bases of Salmonella entry into host cells. Mol. Microbiol., 1996, 20(2), 263-271.
[http://dx.doi.org/10.1111/j.1365-2958.1996.tb02615.x] [PMID: 8733226]
[3]
Jones, B.D.; Falkow, S. Salmonellosis: host immune responses and bacterial virulence determinants. Annu. Rev. Immunol., 1996, 14, 533-561.
[http://dx.doi.org/10.1146/annurev.immunol.14.1.533] [PMID: 8717524]
[4]
Parkhill, J.; Dougan, G.; James, K.D.; Thomson, N.R.; Pickard, D.; Wain, J.; Churcher, C.; Mungall, K.L.; Bentley, S.D.; Holden, M.T.; Sebaihia, M.; Baker, S.; Basham, D.; Brooks, K.; Chillingworth, T.; Connerton, P.; Cronin, A.; Davis, P.; Davies, R.M.; Dowd, L.; White, N.; Farrar, J.; Feltwell, T.; Hamlin, N.; Haque, A.; Hien, T.T.; Holroyd, S.; Jagels, K.; Krogh, A.; Larsen, T.S.; Leather, S.; Moule, S.; O’Gaora, P.; Parry, C.; Quail, M.; Rutherford, K.; Simmonds, M.; Skelton, J.; Stevens, K.; Whitehead, S.; Barrell, B.G. Complete genome sequence of a multiple drug resistant Salmonella enterica serovar Typhi CT18. Nature, 2001, 413(6858), 848-852.
[http://dx.doi.org/10.1038/35101607] [PMID: 11677608]
[5]
Rowe, B.; Ward, L.R.; Threlfall, E.J. Multidrug-resistant Salmonella typhi: a worldwide epidemic. Clin. Infect. Dis., 1997, 24(Suppl. 1), S106-S109.
[http://dx.doi.org/10.1093/clinids/24.Supplement_1.S106] [PMID: 8994789]
[6]
Maiti, S.; Patro, S.; Purohit, S.; Jain, S.; Senapati, S.; Dey, N. Effective control of Salmonella infections by employing combinations of recombinant antimicrobial human β-defensins hBD-1 and hBD-2. Antimicrob. Agents Chemother., 2014, 58(11), 6896-6903.
[http://dx.doi.org/10.1128/AAC.03628-14] [PMID: 25199778]
[7]
Wain, J.; Diep, T.S.; Ho, V.A.; Walsh, A.M.; Nguyen, T.T.; Parry, C.M.; White, N.J. Quantitation of bacteria in blood of typhoid fever patients and relationship between counts and clinical features, transmissibility, and antibiotic resistance. J. Clin. Microbiol., 1998, 36(6), 1683-1687.
[PMID: 9620400]
[8]
Karamat, K.A. Karamat KA. Multiple drug resistant Salmonella typhi and ciprofloxacin. In: Proceedings of the 2nd Western Pacific Congress on Infectious Diseases and Chemotherapy. Jakarta, Indonesia: Western Pacific Society of Chemotherapy,, 1990, p. 480.
[9]
Lancet. B.M.-T. Treatment of Multiresistant Typhoid Fever. thelancet.com; Accessed, 1990.
[10]
Madhavang, H.N.; Bogyalakshmi, R. Farewell, Chloramphenicol? Is This True?: A Review. Res. Rev. J. Microbiol. Biotechnol., 1970, 3, 13-26.
[11]
Kapil, A. The challenge of antibiotic resistance: need to contemplate. Indian J. Med. Res., 2005, 121(2), 83-91.
[PMID: 15756040]
[12]
Steinberg, E. Antimicrobial Resistance of Salmonella typhi in the United States: the National Antimicrobial Monitoring System (NARMS), 1999. Google Search.
[13]
Parry, C.; Wain, J.; Chinh, N.T.; Vinh, H.; Farrar, J.J. Quinolone-resistant Salmonella typhi in Vietnam. Lancet, 1998, 351(9111), 1289.
[http://dx.doi.org/10.1016/S0140-6736(05)79356-9] [PMID: 9643778]
[14]
Deng, W.; Liou, S.; Iii, G.P.; Mayhew, G.F.; Rose, D.J.; Burland, V.; Kodoyianni, V.; Schwartz, D.C.; Blattner, F.R. Comparative genomics of salmonella enterica serovar typhi strains TY2 and CT18. J. Bacteriol., 2003, 185, 2330-2337.
[15]
Huang, Y.; Niu, B.; Gao, Y.; Fu, L.; Li, W. CD-HIT Suite : A web server for clustering and comparing biological sequences. Bioinformatics, 2010, 26(5), 680-682.
[http://dx.doi.org/10.1093/bioinformatics/btq003]
[16]
Su, M.; Ling, Y.; Yu, J.; Wu, J.; Xiao, J.; Wang, X.; United, H. Small proteins: untapped area of potential biological importance. Front. Genet., 2013, 4, 286.
[http://dx.doi.org/10.3389/fgene.2013.00286] [PMID: 24379829]
[17]
Singh Sarita, G.S.K.; Pant, K.K.G.M.K.; Kumar, G.M. K, P.K.; K, S.P. Definition of Potential targets in mycoplasma pneumoniae through subtractive genome analysis. J. Antivir. Antiretrovir., 2010, 2(2)
[http://dx.doi.org/10.4172/jaa.100002]
[18]
Haag, N.L. Velk, K.K.; Wu C. In silico identification of drug targets in methicillin/multidrug-resistant staphylococcus aureus. Biotechno., 2011, 4, 91-99.
[19]
Hossain, M.; Chowdhury, D.U.S.; Farhana, J.; Akbar, M.T.; Chakraborty, A.; Islam, S.; Mannan, A. Identification of potential targets in Staphylococcus aureus N315 using computer aided protein data analysis. Bioinformation, 2013, 9(4), 187-192.
[http://dx.doi.org/10.6026/97320630009187] [PMID: 23519164]
[20]
Kerfeld, C.A.; Scott, K.M. Using BLAST to teach “E-value-tionary” concepts. PLoS Biol., 2011, 9(2)e1001014
[http://dx.doi.org/10.1371/journal.pbio.1001014] [PMID: 21304918]
[21]
Zhang, R.; Ou, H-Y.; Zhang, C-T. DEG: a database of essential genes. Nucleic Acids Res., 2004, 32(Database issue), D271-D272.
[http://dx.doi.org/10.1093/nar/gkh024] [PMID: 14681410]
[22]
Zhang, R.; Lin, Y. DEG 5.0, a database of essential genes in both prokaryotes and eukaryotes. Nucleic Acids Res., 2009, 37(Database issue), D455-D458.
[http://dx.doi.org/10.1093/nar/gkn858] [PMID: 18974178]
[23]
Moriya, Y.; Itoh, M.; Okuda, S.; Yoshizawa, A.C.; Kanehisa, M. KAAS: an automatic genome annotation and pathway reconstruction server. Nucleic Acids Res, 2007. 35(Web Server issue), W182- W185.
[http://dx.doi.org/10.1093/nar/gkm321] [PMID: 17526522]
[24]
Yu, N.Y.; Wagner, J.R.; Laird, M.R.; Melli, G.; Rey, S.; Lo, R.; Dao, P.; Sahinalp, S.C.; Ester, M.; Foster, L.J.; Brinkman, F.S.L. PSORTb 3.0: improved protein subcellular localization prediction with refined localization subcategories and predictive capabilities for all prokaryotes. Bioinformatics, 2010, 26(13), 1608-1615.
[http://dx.doi.org/10.1093/bioinformatics/btq249] [PMID: 20472543]
[25]
Bakheet, T.M.; Doig, A.J. Properties and identification of antibiotic drug targets. BMC Bioinformatics, 2010, 11, 195.
[http://dx.doi.org/10.1186/1471-2105-11-195] [PMID: 20406434]
[26]
Garmory, H.S.; Titball, R.W. ATP-binding cassette transporters are targets for the development of antibacterial vaccines and therapies. Infect. Immun., 2004, 72(12), 6757-6763.
[http://dx.doi.org/10.1128/IAI.72.12.6757-6763.2004] [PMID: 15557595]
[27]
Yu, C-S.; Lin, C-J.; Hwang, J-K. Predicting subcellular localization of proteins for Gram-negative bacteria by support vector machines based on n-peptide compositions. Protein Sci., 2004, 13(5), 1402-1406.
[http://dx.doi.org/10.1110/ps.03479604] [PMID: 15096640]
[28]
Arinaminpathy, Y.; Khurana, E.; Engelman, D.M.; Gerstein, M.B. Computational analysis of membrane proteins: the largest class of drug targets. Drug Discov. Today, 2009, 14(23-24), 1130-1135.
[http://dx.doi.org/10.1016/j.drudis.2009.08.006] [PMID: 19733256]
[29]
Chen, L.; Xiong, Z.; Sun, L.; Yang, J.; Jin, Q. VFDB 2012 update: toward the genetic diversity and molecular evolution of bacterial virulence factors. Nucleic Acids Res., 2012, 40(Database issue), D641-D645.
[http://dx.doi.org/10.1093/nar/gkr989] [PMID: 22067448]
[30]
Chen, L.; Zheng, D.; Liu, B.; Yang, J.; Jin, Q. VFDB 2016 : Hierarchical and refined dataset for big data analysis - 10 Years On. Nucleic Acids Res., 2016, 44(Database issue), D694-D697.
[31]
Law, V.; Knox, C.; Djoumbou, Y.; Jewison, T.; Guo, A.C.; Liu, Y.; Maciejewski, A.; Arndt, D.; Wilson, M.; Neveu, V.; Tang, A.; Gabriel, G.; Ly, C.; Adamjee, S.; Dame, Z.T.; Han, B.; Zhou, Y.; Wishart, D.S. DrugBank 4.0: shedding new light on drug metabolism. Nucleic Acids Res., 2014, 42(Database issue), D1091-D1097.
[http://dx.doi.org/10.1093/nar/gkt1068] [PMID: 24203711]
[32]
Knox, C.; Law, V.; Jewison, T.; Liu, P.; Ly, S.; Frolkis, A.; Pon, A.; Banco, K.; Mak, C.; Neveu, V.; Djoumbou, Y.; Eisner, R.; Guo, A.C.; Wishart, D.S. DrugBank 3. 0 : A Comprehensive Resource for ‘ Omics ’. Research on Drugs., 2011, 39, 1035-1041.
[33]
Wishart, D.S.; Knox, C.; Guo, A.C.; Shrivastava, S.; Hassanali, M.; Stothard, P.; Chang, Z.; Woolsey, J.; Tg, C. DrugBank : A comprehensive resource for in silico drug discovery and exploration. Nucleic Acids Res., 2006, 34, D668-D672.
[http://dx.doi.org/10.1093/nar/gkj067]
[34]
Wishart, D.S.; Knox, C.; Guo, A.C.; Cheng, D.; Shrivastava, S.; Tzur, D.; Gautam, B.; Hassanali, M.; Tg, C. DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res., 2008, 36(Database issue), D901-D906.
[http://dx.doi.org/10.1093/nar/gkm958] [PMID: 18048412]
[35]
Yang, Y.; Gao, P.; Liu, Y.; Ji, X.; Gan, M.; Guan, Y.; Hao, X.; Li, Z.; Xiao, C. A discovery of novel Mycobacterium tuberculosis pantothenate synthetase inhibitors based on the molecular mechanism of actinomycin D inhibition. Bioorg. Med. Chem. Lett., 2011, 21(13), 3943-3946.
[http://dx.doi.org/10.1016/j.bmcl.2011.05.021] [PMID: 21641210]
[36]
Chiranjeevi, P.; Chandra, C.; Reddy, S.; Kumar, K.S.; Madhulitha, N.R.; Bitla, A.R.; Umamaheswari, A. An in Silico Study: novel targets for potential drug and vaccine design against drug resistant H. pylori. Microb. Pathog., 2018, 122, 156-161.
[37]
Anishetty, S.; Pulimi, M.; Pennathur, G. Potential drug targets in mycobacterium tuberculosis through metabolic pathway analysis. Comput. Biol. Chem., 2005, 29(5), 368-378.
[http://dx.doi.org/10.1016/j.compbiolchem.2005.07.001]
[38]
Barh, D.; Kumar, A. In silico identification of candidate drug and vaccine targets from various pathways in Neisseria gonorrhoeae. In: In Silico Biol. (Gedrukt); , 2009; 9, pp. (4)225-231.
[PMID: 20109152]
[39]
Barh, D.; Tiwari, S.; Jain, N.; Ali, A.; Santos, A.; Misra, A.N.; Azevedo, V.; Kumar, A. In silico subtractive genomics for target identification in human bacterial pathogens. Drug Dev. Res., 2010, 72(2), 162-177.
[http://dx.doi.org/10.1002/ddr.20413.]
[40]
Ludin, P.; Woodcroft, B.; Ralph, S.A.; Mäser, P. In silico prediction of antimalarial drug target candidates. Int. J. Parasitol. Drugs Drug Resist., 2012, 2, 191-199.
[http://dx.doi.org/10.1016/j.ijpddr.2012.07.002] [PMID: 24533280]
[41]
Jensen, L.J.; Kuhn, M.; Stark, M.; Chaffron, S.; Creevey, C.; Muller, J.; Doerks, T.; Julien, P.; Roth, A.; Simonovic, M.; Bork, P.; von Mering, C. STRING 8--a global view on proteins and their functional interactions in 630 organisms. Nucleic Acids Res., 2009, 37(Database issue), D412-D416.
[http://dx.doi.org/10.1093/nar/gkn760] [PMID: 18940858]
[42]
Dervartanian, D.V.; Forget, P. The Bacterial Nitrate Reductase EPR Studies on the Enzyme a of Escherichia Coli K12. Biochim. Biophys. Acta Protein Struct., 1975, 379, 74-80.
[http://dx.doi.org/10.1016/0005-2795(75)90009-4]
[43]
Anderson, L.J.; Richardson, D.J.; Butt, J.N. Using direct electrochemistry to probe rate limiting events during nitrate reductase turnover. Faraday Discuss., 2000, 116(116), 155-169.
[http://dx.doi.org/10.1039/b000946f] [PMID: 11197477]
[44]
Yoshimatsu, K.; Iwasaki, T.; Fujiwara, T. Sequence and electron paramagnetic resonance analyses of nitrate reductase NarGH from a denitrifying halophilic euryarchaeote Haloarcula marismortui. FEBS Lett., 2002, 516(1-3), 145-150.
[http://dx.doi.org/10.1016/S0014-5793(02)02524-3] [PMID: 11959121]
[45]
Correia, C.; Besson, S.; Brondino, C.D.; González, P.J.; Fauque, G.; Lampreia, J.; Moura, I.; Moura, J.J.G. Biochemical and spectroscopic characterization of the membrane-bound nitrate reductase from Marinobacter hydrocarbonoclasticus 617. J. Biol. Inorg. Chem., 2008, 13(8), 1321-1333.
[http://dx.doi.org/10.1007/s00775-008-0416-1] [PMID: 18704520]
[46]
Li, Z.; Lou, H.; Ojcius, D.M.; Sun, A.; Sun, D.; Zhao, J.; Lin, X.; Yan, J. Methyl-accepting chemotaxis proteins 3 and 4 are responsible for Campylobacter jejuni chemotaxis and jejuna colonization in mice in response to sodium deoxycholate. J. Med. Microbiol., 2014, 63(Pt 3), 343-354.
[http://dx.doi.org/10.1099/jmm.0.068023-0] [PMID: 24403598]
[47]
Hosen, I.; Tanmoy, A.M.; Mahbuba, D.; Salma, U. Application of a subtractive genomics approach for in silico identification and characterization of novel drug targets in mycobacterium tuberculosis F11. Interdiscip. Sci., 2014, 6(1), 48-56.
[http://dx.doi.org/10.1007/s12539-014-0188-y]
[48]
Narayan Sarangi, A. Subtractive genomics approach for in silico identification and characterization of novel drug targets in neisseria meningitides serogroup B. J. Comput. Sci. Syst. Biol., 2009, 02, 255-258.
[http://dx.doi.org/10.4172/jcsb.1000038]
[49]
Barrett, J.F.; Hoch, J.A. Two-component signal transduction as a target for microbial anti-infective therapy. Antimicrob. Agents Chemother., 1998, 42(7), 1529-1536.
[http://dx.doi.org/10.1128/AAC.42.7.1529] [PMID: 9660978]
[50]
Cai, X.H.; Zhang, Q.; Shi, S.Y.; Ding, D.F. Searching for potential drug targets in two-component and phosphorelay signal-transduction systems using three-dimensional cluster analysis. Acta Biochim. Biophys. Sin. (Shanghai), 2005, 37(5), 293-302.
[http://dx.doi.org/10.1111/j.1745-7270.2005.00046.x] [PMID: 15880257]
[51]
Amineni, U. Pradhan, D.; Marisetty. H. In Silico Identification of Common Putative Drug Targets in Leptospira Interrogans. J. Chem. Biol., 2010, 3(4), 165-173.


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VOLUME: 19
ISSUE: 29
Year: 2019
Published on: 26 December, 2019
Page: [2708 - 2717]
Pages: 10
DOI: 10.2174/1568026619666191105102156
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