Skip to main content
Log in

Investigations on the Interactions of λPhage-Derived Peptides Against the SrtA Mechanism in Bacillus anthracis

  • Published:
Applied Biochemistry and Biotechnology Aims and scope Submit manuscript

Abstract

Bacillus anthracis is a well-known bioweapon pathogen, which coordinates the expression of its virulence factors in response to a specific environmental signal by its protein architecture. Absences of sortase signal functioning may fail to assemble the surface linked proteins and so B. anthracis cannot sustain an infection with host cells. Targeting the signaling mechanism of B. anthracis can be achieved by inhibition of SrtA enzyme through λphage-derived plyG. The lysin enzyme plyG is experimentally proven as bacteriolytic agent, specifically kill's B. anthracis by inhibiting the SrtA. Here, we have screened the peptides from λphage lysin, and these peptides are having the ability as LPXTG competitive inhibitors. In comparison to the activator peptide LPXTG binding motif, λphage lysin based inhibitor peptides are having much supremacy towards binding of SrtA. Finally, peptide structures extracted from PlyG are free from toxic, allergic abilities and also have the ability to terminate the signal transduction mechanism in B. anthracis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Franz, D. R. (2009). Preparedness for an anthrax attack. Molecular Aspects of Medicine, 30, 503–510.

    Article  CAS  Google Scholar 

  2. Nicholson, W. L., Munakata, N., Horneck, G., Melosh, H. J., & Setlow, P. (2000). Resistance of Bacillus endospores to extreme terrestrial and extraterrestrial environments. Microbiology and Molecular Biology Reviews, 64, 548–572.

    Article  CAS  Google Scholar 

  3. Klietmann, W. F., & Ruoff, K. L. (2001). Bioterrorism: implications for the clinical microbiologist. Clinical Microbiology Reviews, 14, 364–381.

    Article  CAS  Google Scholar 

  4. Marraffini, L. A., Dedent, A. C., & Schneewind, O. (2006). Sortases and the art of anchoring proteins to the envelopes of gram-positive bacteria. Microbiology and Molecular Biology Reviews, 70, 192–221.

    Article  CAS  Google Scholar 

  5. Mazmanian, S. K., Ton-That, H., Su, K., & Schneewind, O. (2002). An iron-regulated sortase anchors a class of surface protein during Staphylococcus aureus pathogenesis. Proceedings of the National Academy of Sciences of the United States of America, 99, 2293–2298.

    Article  CAS  Google Scholar 

  6. Chopra, I., Hodgson, J., Metcalf, B., & Poste, G. (1997). The search for antimicrobial agents effective against bacteria resistant to multiple antibiotics. Antimicrobial Agents and Chemotherapy, 41, 497–503.

    CAS  Google Scholar 

  7. Mogridge, J. (2007). Defensive strategies of Bacillus anthracis that promote a fatal disease. Drug Discovery Today Discovery Mechanism, 4, 253–258.

    Article  Google Scholar 

  8. Lashley, F. R. (2004). Emerging infectious diseases: vulnerabilities, contributing factors and approaches. Expert Review of Anti-Infective Therapy, 2, 299–316.

    Article  Google Scholar 

  9. Ormala, A. M., & Jalasvuori, M. (2013). Phage therapy: should bacterial resistance to phages be a concern, even in the long run? Bacteriophage, 3, e24219.

    Article  Google Scholar 

  10. Burrowes, B., Harper, D. R., Anderson, J., McConville, M., & Enright, M. C. (2011). Bacteriophage therapy: potential uses in the control of antibiotic-resistant pathogens. Expert Review of Anti-Infective Therapy, 9, 775–785.

    Article  Google Scholar 

  11. Schuch, R., Nelson, D., & Fischetti, V. A. (2002). A bacteriolytic agent that detects and kills Bacillus anthracis. Nature, 418, 884–889.

    Article  CAS  Google Scholar 

  12. Rosovitz, M. J., & Leppla, S. H. (2002). Virus deals anthrax a killer blow. Nature, 418, 825–826.

    Article  CAS  Google Scholar 

  13. Schuch, R., Pelzek, A. J., Raz, A., Euler, C. W., Ryan, P. A., Winer, B. Y., Farnsworth, A., Bhaskaran, S. S., Stebbins, C. E., Xu, Y., Clifford, A., Bearss, D. J., Vankayalapati, H., Goldberg, A. R., & Fischetti, V. A. (2013). Use of a bacteriophage lysin to identify a novel target for antimicrobial development. PLoS One, 8, e60754.

    Article  CAS  Google Scholar 

  14. Kikkawa, H. S., Ueda, T., Suzuki, S., & Yasuda, J. (2008). Characterization of the catalytic activity of the gamma-phage lysin, PlyG, specific for Bacillus anthracis. FEMS Microbiology Letters, 286, 236–240.

    Article  CAS  Google Scholar 

  15. Fujinami, Y., Hirai, Y., Sakai, I., Yoshino, M., & Yasuda, J. (2007). Sensitive detection of Bacillus anthracis using a binding protein originating from gamma-phage. Microbiology and Immunology, 51, 163–169.

    Article  CAS  Google Scholar 

  16. Fischetti, V. A. (2005). Bacteriophage lytic enzymes: novel anti-infectives. Trends in Microbiology, 13, 491–496.

    Article  CAS  Google Scholar 

  17. Mo, K. F., Li, X., Li, H., Low, L. Y., Quinn, C. P., & Boons, G. J. (2012). Endolysins of Bacillus anthracis bacteriophages recognize unique carbohydrate epitopes of vegetative cell wall polysaccharides with high affinity and selectivity. Journal of the American Chemical Society, 134, 15556–15562.

    Article  CAS  Google Scholar 

  18. Hermoso, J. A., Garcia, J. L., & Garcia, P. (2007). Taking aim on bacterial pathogens: from phage therapy to enzybiotics. Current Opinion in Microbiology, 10, 461–472.

    Article  CAS  Google Scholar 

  19. Ganguly, J., Low, L. Y., Kamal, N., Saile, E., Forsberg, L. S., Gutierrez-Sanchez, G., Hoffmaster, A. R., Liddington, R., Quinn, C. P., Carlson, R. W., & Kannenberg, E. L. (2013). The secondary cell wall polysaccharide of Bacillus anthracis provides the specific binding ligand for the C-terminal cell wall-binding domain of two phage endolysins, PlyL and PlyG. Glycobiology, 23, 820–832.

    Article  CAS  Google Scholar 

  20. Davison, S., Couture-Tosi, E., Candela, T., Mock, M., & Fouet, A. (2005). Identification of the Bacillus anthracis (gamma) phage receptor. Journal of Bacteriology, 187, 6742–6749.

    Article  CAS  Google Scholar 

  21. Low, L. Y., Yang, C., Perego, M., Osterman, A., & Liddington, R. (2011). Role of net charge on catalytic domain and influence of cell wall binding domain on bactericidal activity, specificity, and host range of phage lysins. The Journal of Biological Chemistry, 286, 34391–34403.

    Article  CAS  Google Scholar 

  22. Ton-That, H., Marraffini, L. A., & Schneewind, O. (2004). Protein sorting to the cell wall envelope of Gram-positive bacteria. Biochimica et Biophysica Acta, 1694, 269–278.

    Article  CAS  Google Scholar 

  23. Dramsi, S., Trieu-Cuot, P., & Bierne, H. (2005). Sorting sortases: a nomenclature proposal for the various sortases of Gram-positive bacteria. Research in Microbiology, 156, 289–297.

    Article  CAS  Google Scholar 

  24. Ton-That, H., & Schneewind, O. (2004). Assembly of pili in Gram-positive bacteria. Trends in Microbiology, 12, 228–234.

    Article  CAS  Google Scholar 

  25. Hendrickx, A. P., Budzik, J. M., Oh, S. Y., & Schneewind, O. (2011). Architects at the bacterial surface—sortases and the assembly of pili with isopeptide bonds. Nature Reviews Microbiology, 9, 166–176.

    Article  CAS  Google Scholar 

  26. Bhasin, M., & Raghava, G. P. (2004). SVM based method for predicting HLA-DRB1*0401 binding peptides in an antigen sequence. Bioinformatics, 20, 421–423.

    Article  CAS  Google Scholar 

  27. Weiner, E. M., Robson, S., Marohn, M., & Clubb, R. T. (2010). The Sortase A enzyme that attaches proteins to the cell wall of Bacillus anthracis contains an unusual active site architecture. The Journal of Biological Chemistry, 285, 23433–23443.

    Article  CAS  Google Scholar 

  28. Reddy, K. K., Singh, S. K., Tripathi, S. K., & Selvaraj, C. (2013). Identification of potential HIV-1 integrase strand transfer inhibitors: in silico virtual screening and QM/MM docking studies. SAR and QSAR in Environmental Research, 24, 581–595.

    Article  CAS  Google Scholar 

  29. Georgiev, V., Noack, H., Borowski, T., Blomberg, M. R., & Siegbahn, P. E. (2010). DFT study on the catalytic reactivity of a functional model complex for intradiol-cleaving dioxygenases. The Journal of Physical Chemistry. B, 114, 5878–5885.

    Article  CAS  Google Scholar 

  30. Pissarnitski, D. A., Asberom, T., Bara, T. A., Buevich, A. V., Clader, J. W., Greenlee, W. J., Guzik, H. S., Josien, H. B., Li, W., McEwan, M., McKittrick, B. A., Nechuta, T. L., Parker, E. M., Sinning, L., Smith, E. M., Song, L., Vaccaro, H. A., Voigt, J. H., Zhang, L., Zhang, Q., & Zhao, Z. (2007). 2,6-Disubstituted N-arylsulfonyl piperidines as gamma-secretase inhibitors. Bioorganic and Medicinal Chemistry Letters, 17, 57–62.

    Article  CAS  Google Scholar 

  31. Fu, J., Si, P., Zheng, M., Chen, L., Shen, X., Tang, Y., & Li, W. (2012). Discovery of new non-steroidal FXR ligands via a virtual screening workflow based on Phase shape and induced fit docking. Bioorganic and Medicinal Chemistry Letters, 22, 6848–6853.

    Article  CAS  Google Scholar 

  32. Abell, A. D., Jones, M. A., Neffe, A. T., Aitken, S. G., Cain, T. P., Payne, R. J., McNabb, S. B., Coxon, J. M., Stuart, B. G., Pearson, D., Lee, H. Y., & Morton, J. D. (2007). Investigation into the P3 binding domain of m-calpain using photoswitchable diazo- and triazene-dipeptide aldehydes: new anticataract agents. Journal of Medicinal Chemistry, 50, 2916–2920.

    Article  CAS  Google Scholar 

  33. Selvaraj, C., Singh, S. K., Tripathi, S. K., Reddy, K. K., & Rama, M. (2012). In silico screening of indinavir-based compounds targeting proteolytic activity in HIV PR: binding pocket fit approach. Medicinal Chemistry Research, 21, 4060–4068.

    Article  CAS  Google Scholar 

  34. Das, D., Koh, Y., Tojo, Y., Ghosh, A. K., & Mitsuya, H. (2009). Prediction of potency of protease inhibitors using free energy simulations with polarizable quantum mechanics-based ligand charges and a hybrid water model. Journal of Chemical Information and Modeling, 49, 2851–2862.

    Article  CAS  Google Scholar 

  35. Tripathi, S. K., Singh, S. K., Singh, P., Chellaperumal, P., Reddy, K. K., & Selvaraj, C. (2012). Exploring the selectivity of a ligand complex with CDK2/CDK1: a molecular dynamics simulation approach. Journal of Molecular Recognition, 25, 504–512.

    Article  CAS  Google Scholar 

  36. Selvaraj, C. and Singh, S. K. Validation of potential inhibitors for SrtA against Bacillus anthracis by combined approach of ligand-based and molecular dynamics simulation. J Biomol Struct Dyn. doi:10.1080/07391102.2013.818577

  37. Shafreen, R. M., Selvaraj, C., Singh, S. K., & Pandian, S. K. (2013). Exploration of fluoroquinolone resistance in Streptococcus pyogenes: comparative structure analysis of wild-type and mutant DNA gyrase. Journal of Molecular Recognition, 26, 276–285.

    Article  CAS  Google Scholar 

  38. Pronk, S., Pall, S., Schulz, R., Larsson, P., Bjelkmar, P., Apostolov, R., Shirts, M. R., Smith, J. C., Kasson, P. M., van der Spoel, D., Hess, B., & Lindahl, E. (2013). GROMACS 4.5: a high-throughput and highly parallel open source molecular simulation toolkit. Bioinformatics, 29, 845–854.

    Article  CAS  Google Scholar 

  39. Dearden, J. C. (2003). In silico prediction of drug toxicity. Journal of Computer-Aided Molecular Design, 17, 119–127.

    Article  CAS  Google Scholar 

  40. Cronin, M. T. (2001). Prediction of drug toxicity. Farmaco, 56, 149–151.

    Article  CAS  Google Scholar 

  41. Mombelli, E. (2008). An evaluation of the predictive ability of the QSAR software packages, DEREK, HAZARDEXPERT and TOPKAT, to describe chemically-induced skin irritation. Alternatives to Laboratory Animals, 36, 15–24.

    CAS  Google Scholar 

  42. Vijayalakshmi, P., Selvaraj, C., Singh, S. K., Nisha, J., Saipriya, K., & Daisy, P. (2012). Exploration of the binding of DNA binding ligands to Staphylococcal DNA through QM/MM docking and molecular dynamics simulation. Journal of Biomolecular Structure and Dynamics, 31, 561–571.

    Article  Google Scholar 

  43. Dimitrov, I., Flower, D. R. and Doytchinova, I. (2013) AllerTOP—a server for in silico prediction of allergens. BMC Bioinformatics, 14 Suppl 6, S4.

  44. Huang, L., & Chen, C. H. (2009). Proteasome regulators: activators and inhibitors. Current Medicinal Chemistry, 16, 931–939.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

The authors thankfully acknowledge the CSIR for research funding and fellowship grants (Ref. No: 37(1491)/11/EMR-II). One of the authors Chandrabose Selvaraj gratefully acknowledges CSIR for the Senior Research Fellowship (SRF). The authors thank anonymous referees for the valuable suggestion on this research work.

Conflict of Interests

None

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sanjeev Kumar Singh.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Selvaraj, C., Singh, P. & Singh, S.K. Investigations on the Interactions of λPhage-Derived Peptides Against the SrtA Mechanism in Bacillus anthracis . Appl Biochem Biotechnol 172, 1790–1806 (2014). https://doi.org/10.1007/s12010-013-0641-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12010-013-0641-0

Keywords

Navigation