Streptococcus pyogenes is one of the most important pathogens as it is involved in various infections affecting upper respiratory tract and skin. Due to the emergence of multidrug resistance and cross-resistance, S. Pyogenes is becoming more pathogenic and dangerous. In the present study, an in silico comparative analysis of total 65 metabolic pathways of the host (Homo sapiens) and the pathogen was performed. Initially, 486 paralogous enzymes were identified so that they can be removed from possible drug target list. The 105 enzymes of the biochemical pathways of S. pyogenes from the KEGG metabolic pathway database were compared with the proteins from the Homo sapiens by performing a BLASTP search against the non-redundant database restricted to the Homo sapiens subset. Out of these, 83 enzymes were identified as non-human homologous while 30 enzymes of inadequate amino acid length were removed for further processing. Essential enzymes were finally mined from remaining 53 enzymes. Finally, 28 essential enzymes were identified in S. pyogenes SF370 (serotype M1). In subcellular localization study, 18 enzymes were predicted with cytoplasmic localization and ten enzymes with the membrane localization. These ten enzymes with putative membrane localization should be of particular interest. Acyl-carrier-protein S-malonyltransferase, DNA polymerase III subunit beta and dihydropteroate synthase are novel drug targets and thus can be used to design potential inhibitors against S. pyogenes infection. 3D structure of dihydropteroate synthase was modeled and validated that can be used for virtual screening and interaction study of potential inhibitors with the target enzyme.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Price excludes VAT (USA)
Tax calculation will be finalised during checkout.
Suvrov AN, Ferretti JJ (1996) Physical and genetic map of an M type 1 strain of Streptococcus pyogenes. J Bacteriol 178:5546–5549
Bisno AL, Brito MO, Collins CM (2003) Molecular basis of group A streptococcal virulence. Lancet Infect Dis 3:191–200
Fiedler T, Köller T, Kreikemeyer B (2015) Streptococcus pyogenes biofilms formation, biology, and clinical relevance. Front Cell Infect Microbiol. doi:10.3389/fcimb.2015.00015
Fan J, Dong L, Chen Z, Bei D (2014) Clinical characteristics and antimicrobial resistance of invasive group A β-hemolytic streptococcus infection in children. Zhonghua Er Ke Za Zhi 52:46–50
Ferretti JJ, McShan WM, Ajdic D, Savic DJ, Savic G, Lyon K, Primeaux C et al (2001) Complete genome sequence of an M1 strain of Streptococcus pyogenes. Proc Natl Acad Sci USA 98:4658–4663
Kanehisa M, Goto S, Kawashima S, Nakaya A (2002) The KEGG databases at genome net. Nucl Acids Res 30:42–46
Altschul SF, Madden TL, Schäffer AA, Zhang J, Zhang Z, Miller W, Lipman DJ (1997) Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucl Acids Res 25:3389–3402
Singh S, Singh G, Sagar N, Yadav PK, Jain PA, Gautam B, Wadhwa G (2012) Insight into Trichomonas vaginalis genome evolution through metabolic pathways comparison. Bioinformation 8:189–195
Yu CS, Chen YC, Lu CH, Hwang JK (2006) Prediction of protein subcellular localization. Proteins Struct Funct Bioinform 64:643–651
Yu CS, Lin CJ, Hwang JK (2004) Predicting subcellular localization of proteins for Gram-negative bacteria by support vector machines based on n-peptide compositions. Protein Sci 13:1402–1406
Eswar N, Webb B, Marti-Renom MA, Madhusudhan MS, Eramian D, Shen MY, Pieper U, Sali A (2007) Comparative protein structure modeling using MODELLER. Curr Protoc Protein Sci. doi:10.1002/0471140864.ps0209s50
Lüthy R, Bowie JU, Eisenberg D (1992) Assessment of protein models with three-dimensional profiles. Nature 356:83–85
Laskowski RA, Rullmannn JA, MacArthur MW, Kaptein R, Thornton JM (1996) AQUA and PROCHECK-NMR: programs for checking the quality of protein structures solved by NMR. J Biomol NMR 8:477–486
Colovos C, Yeates TO (1993) Verification of protein structures: patterns of nonbonded atomic interactions. Protein Sci 2:1511–1519
Wiederstein M, Sippl MJ (2007) ProSA-web: interactive web service for the recognition of errors in three-dimensional structures of proteins. Nucleic Acids Res 35(Web Server issue):W407–W410
Singh S, Singh G, Gautam B, Jain PA, Yadav PK (2011) In silico metabolic pathway analysis of Trichomonas vaginalis for potential drug targets. Elixir Biol Phys 32:1991–1994
Zhang L, Liu W, Xiao J, Hu T, Chen J, Chen K, Jiang H, Shen X (2007) Malonyl-CoA: acyl carrier protein transacylase from Helicobacter pylori: crystal structure and its interaction with acyl carrier protein. Protein Sci 16:1184–1192
Gui WJ, Lin SQ, Chen YY, Zhang XE, Bi LJ, Jiang T (2011) Crystal structure of DNA polymerase III β sliding clamp from Mycobacterium tuberculosis. Biochem Biophys Res Commun 405:272–277
Subbayya IN, Ray SS, Balaram P, Balaram H (1997) Metabolic enzymes as potential drug targets in Plasmodium falciparum. Indian J Med Res 106:79–94
Dias MV, Ely F, Palma MS, de Azevedo WF, LA Jr Basso, Santos DS (2007) Chorismate synthase: an attractive target for drug development against orphan diseases. Curr Drug Targets 8:437–444
Vidya N, Vadivukkarasi B, Manivannan G, Anbarasu K (2008) Molecular modeling and docking studies of glutamate racemase in Vibrio vulnificus CMCP6. In Silico Biol 8:471–483
Zíková A, Schnaufer A, Dalley RA, Panigrahi AK, Stuart KD (2009) The F(0)F(1)-ATP synthase complex contains novel subunits and is essential for procyclic Trypanosoma brucei. PLoS Pathog. doi:10.1371/journal.ppat.1000436
Iliades P, Meshnick SR, Macreadie IG (2004) Dihydropteroate synthase mutations in Pneumocystis jiroveci can affect sulfamethoxazole resistance in a Saccharomyces cerevisiae model. Antimicrob Agents Chemother 48:2617–2623
Olabisi OC, Prasit P (2011) Current understanding of de novo synthesis of bacterial lipid carrier (undecaprenyl phosphate): more enzymes to be discovered. Afr J Microbiol Res 5:2555–2565
Achari A, Somers DO, Champness JN, Bryant PK, Rosemond J, Stammers DK (1997) Crystal structure of the anti-bacterial sulfonamide drug target dihydropteroate synthase. Nat Struct Biol 4:490–497
Singh DB, Gupta MK, Kesharwani RK, Sagar M, Dwivedi S, Misra K (2014) Drug targets and therapies for Alzheimer’s disease. Trans Neurol 5:203–217
Singh DB, Gupta MK, Singh DV, Singh SK, Misra K (2013) Docking and in silico ADMET studies of noraristeromycin, curcumin and its derivatives with plasmodium falciparum SAH hydrolase: a molecular drug target against malaria. Interdiscip Sci 5:1–12
Conflict of interest
The authors declare that they have no conflict of interest.
Electronic supplementary material
Below is the link to the electronic supplementary material.
About this article
Cite this article
Singh, S., Singh, D.B., Singh, A. et al. An Approach for Identification of Novel Drug Targets in Streptococcus pyogenes SF370 Through Pathway Analysis. Interdiscip Sci Comput Life Sci 8, 388–394 (2016). https://doi.org/10.1007/s12539-015-0139-2