Acta Scientific Microbiology (ASMI) (ISSN: 2581-3226)

Research Article Volume 3 Issue 3

In Silico Based Approach to Identify Mura as A Potential Drug Target for Leprosy

Aditya Dev*, Mohd Tayyab Adil and Pravindra Kumar

Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand, India

*Corresponding Author: Aditya Dev, Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand, India.

Received: October 18, 2019; Published: February 10, 2020

×

Abstract

  'The search for novel drugs to prevent or treat infections in Mycobacterium is gaining importance due to the emergence of drug resistance. In the present work, we have analyzed the complete genome of Mycobacterium leprae coding for 1605 proteins to identify some novel drug targets using computational methods. The enzymes were screened on the basis of their essentiality in the pathogen as well as on the basis of having least or negligible similarity for that enzyme in the host, Homo sapiens. These possible drug targets were identified for their role in the metabolic pathway of the pathogen. The results were then screened manually and further comparison of those targets against Tropical Disease Research (TDR) database selecting M. tuberculosis as a species of interest was carried out. This comparison against TDR database identified Mur A as a single outcome. Further, molecular modeling and docking was carried out for this enzyme with its natural substrate UDP-N-acetylglucosamine (UNAG) and a known inhibitor T6362 to understand the key residues that could be targeted for building broad spectrum antibiotics. 

Keywords: Drug Targets; Homology Modeling; Leprosy; Mura; Mycobacterium Leprae

×

References

  1. Health Protection Agency Memorandum on Leprosy (2012).
  2. http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002323/
  3. WHO Weekly Epidemiological Record: Global Leprosy Situation (2010).
  4. Sakharkar KR., et al. “A novel genomics approach for the identification of drug targets in pathogens, with special reference to Pseudomonas aeruginosa”. In Silico Biology 4 (2004): 355-360.
  5. Kobayashi K., et al. “Essential Bacillus subtilis genes”. Proceedings of the National Academy of Sciences USA 100 (2003): 4678-4683.
  6. ( http://www.ncbi.nlm.nih.gov/bioproject/90)
  7. ( http://www.genome.jp/kegg/genome.html)
  8. ( http://tdrtargets.org/)
  9. ( http://spdbv.vital-it.ch/)
  10. El Zoeiby A., et al. “Structure and function of the Mur enzymes: development of novel inhibitors”. Molecular Microbiology 47 (2003): 1-12.
  11. Green DW. “The bacterial cell wall as a source of antibacterial targets”. Expert Opinion on Therapeutic Targets 6 (2002): 1-19.
  12. Van Heijenoort J. “Biosynthesis of the bacterial peptidoglycan unit. In Bacterial Cell Wall (Ghuysen JM and Hakenbeck R, eds)”. Elsevier Science BV, Amsterdam 27 (1994): 39-54. 
  13. Van Heijenoort J. “Recent advances in the formation of the bacterial peptidoglycan monomer unit”. Natural Products Reports 18 (2001): 503-519.
  14. Kahan FM., et al. “The mechanism of action of fosfomycin (phosphonomycin)”. Annals of the New York Academy of Sciences 235 (1974): 364-386.
  15. Skarzynski T., et al. “Structure of UDP-N-acetylglucosamine enolpyruvyl transferase, an enzyme essential for the synthesis of bacterial peptidoglycan, complexed with substrate UDP-N-acetylglucosamine and the drug Fosfomycin”. Structure 4.12 (1996): 1465-1474.  
  16. Marquardt JL., et al. “Kinetics, Stoichiometry, and Identification of the Reactive Thiolate in the Inactivation of UDP-GlcNAc Enolpyruvoyl Transferase by the Antibiotic Fosfomycin”. Biochemistry 33 (1994): 10646-10651.
  17. De Smet KA., et al. “Alteration of a single amino acid residue reverses fosfomycin resistance of recombinant MurA from Mycobacterium tuberculosis”. Microbiology 145 (1999): 3177-3184.
  18. Kim DH., et al. “Characterization of a Cys115 to Asp Substitution in the Escherichia coli Cell Wall Biosynthetic Enzyme UDP-GlcNAc Enolpyruvyl Transferase (MurA) That Confers Resistance to Inactivation by the Antibiotic Fosfomycin”. Biochemistry 35.15 (1996): 4923-4928.
  19. McCoy AJ., et al. “In Vitro and In Vivo Functional Activity of Chlamydia MurA, a UDP-N-Acetylglucosamine Enolpyruvyl Transferase Involved in Peptidoglycan Synthesis and Fosfomycin Resistance”. Journal of Bacteriology 185 (2003): 1218-1228.
  20. Eschenburg S., et al. “A New View of the Mechanisms of UDP-N-Acetylglucosamine Enolpyruvyl Transferase (MurA) and 5-Enolpyruvylshikimate-3-phosphate Synthase (AroA) Derived from X-ray Structures of Their Tetrahedral Reaction Intermediate States”. The Journal of Biological Chemistry 278 (2003): 49215-49222. 
  21. Eschenburg S., et al. “Novel Inhibitor That Suspends the Induced Fit Mechanism of UDP-N-acetylglucosamine Enolpyruvyl Transferase (MurA)”. The Journal of Biological Chemistry 280 (2005): 14070-14075.
  22. Samland AK., et al. “Lysine 22 in UDP-N-Acetylglucosamine Enolpyruvyl Transferase from Enterobacter cloacae Is Crucial for Enzymatic Activity and the Formation of Covalent Adducts with the Substrate Phosphoenolpyruvate and the Antibiotic Fosfomycin”. Biochemistry 38 (1999): 13162-13169.
  23. Samland AK., et al. “Asparagine 23 and Aspartate 305 Are Essential Residues in the Active Site of UDP-N-Acetylglucosamine Enolpyruvyl Transferase from Enterobacter cloacae”. Biochemistry 40 (2001): 1550-1559.
  24. Arca P., et al. “Formation of an adduct between fosfomycin and glutathione: a new mechanism of antibiotic resistance in bacteria”. Antimicrobial Agents and Chemotherapy 32 (1988): 1552-1556.
  25. Gautam B., et al. “Metabolic pathway analysis and molecular docking analysis for identification of putative drug targets in Toxoplasma gondii: novel approach”. Bioinformation 8 (2012): 134-141.
  26. Jin BS., et al. “Inhibitory mechanism of novel inhibitors of UDP-Nacetylglucosamine enolpyruvyl transferase from Haemophilus influenza”. Journal of Microbiology and Biotechnology 19 (2009): 1582-1589.
  27. Reeves DS. “Fosfomycin trometamol”. Journal of Antimicrobial Chemotherapy 34 (1994): 853-858.
  28. Rife CL., et al. “Crystal Structure of a Genomically Encoded Fosfomycin Resistance Protein (FosA) at 1.19 Å Resolution by MAD Phasing Off the L-III Edge of Tl”. Journal of the American Chemical Society 124.37 (2002): 11001-11003.
  29. Schonbrunn E., et al. “Interaction of the herbicide glyphosate with its target enzyme 5-enolpyruvylshikimate 3-phosphate synthase in atomic detail”. Proceedings of the National Academy of Sciences of the United States of America 98 (2001): 1376-1380.
  30. Schonbrunn E., et al. “Studies on the conformational changes in the bacterial cell wall biosynthetic enzyme UDP-N-acetylglucosamine enolpyruvyltransferase (MurA)”. European Journal of Biochemistry 253 (1998): 406-412. 
  31. Venkateswaran PS and Wu HC. “Isolation and Characterization of a Phosphonomycin-Resistant Mutant of Escherichia coliK-12”. Journal of Bacteriology 110 (1972): 935-994. 
  32.   http://www.ncbi.nlm.nih.gov/
  33.  SAVES.
  34. Schrödinger, LLC, New York, NY (2009).
×

Citation

Citation: Aditya Dev., et al. “In Silico Based Approach to Identify Mura as A Potential Drug Target for Leprosy". Acta Scientific Microbiology 3.3 (2020): 01-07.



Member In






News and Events


  • Certification for Review
    Acta Scientific certifies the Editors/reviewers for their review done towards the assigned articles of the respective journals.
  • Submission Timeline for March Issue
    The last date for submission of articles for regular Issues is March 10, 2020.
  • Publication Certificate
    Authors will be issued a "Publication Certificate" as a mark of appreciation for publishing their work.
  • Best Article of the Issue
    The Editors will elect one Best Article after each issue release. The authors of this article will be provided with a certificate of “Best Article of the Issue”.
  • Welcoming Article Submission
    Acta Scientific delightfully welcomes active researchers for submission of articles towards the upcoming issue of respective journals.
  • Contact US