Advertisement

Molecular Biology Reports

, Volume 46, Issue 2, pp 1715–1725 | Cite as

Elucidation of marine fungi derived anthraquinones as mycobacterial mycolic acid synthesis inhibitors: an in silico approach

  • Akanksha Sharma
  • M Hayatul Islam
  • Nida Fatima
  • Tarun K. Upadhyay
  • M. Kalim A. Khan
  • Upendra N. Dwivedi
  • Rolee SharmaEmail author
Original Article
  • 177 Downloads

Abstract

Tuberculosis (TB) is a leading cause of mortality amongst infectious diseases. While the anti-TB drugs can cure TB, the non-compliance and rapidly increasing resistance is of serious concern. The study aimed to search novel potent inhibitor(s) against MabA and PKS18 targets of Mycobacterium tuberculosis (M.tb.) by virtual screening of anthraquinones from marine fungi. The target proteins MabA and PKS18 involved in M.tb. mycolic acid biosynthesis were retrieved from RCSB Protein Data Bank. Chemical structures of 100 marine fungal anthraquinones were retrieved from the PubChem database. These were filtered through Lipinski’s rule of five (for druglikeness) and in silico ADME/Tox analysis (for pharmacokinetic properties) and subjected to molecular docking analysis using AutoDock 4.2. The molecular interaction revealed averufin to possess dual inhibitory potential against M.tb. MabA and PKS18 with binding energy of − 8.84 kcal/mol and − 8.23 kcal/mol, and Ki values of 1.79 and 3.12 µM respectively. Averufin exhibits improved drug-like properties, ADMET profile and binding affinity to both targets as compared to control drugs. Our study suggests that averufin a natural anthraquinone, satisfies all the in silico parameters tested and is expected to efficiently inhibit M.tb. mycolic acid pathway. It might therefore emerge as a promising dual-targeted, novel natural anti-TB lead in future.

Keywords

Marine fungi Anthraquinones Mycobacterium tuberculosis Pharmacokinetics Drug likeness Molecular docking 

Notes

Acknowledgements

Authors are thankful to Department of Science and Technology, Govt. of India for infrastructural support to the Department of Biosciences, Integral University under Fund for Improvement of S&T Infrastructure (FIST) program. The Integral University Communication Cell is also gratefully acknowledged for quick and crisp review of manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Global Tuberculosis Report (2017) http://www.who.int/tb/publications /global_report/MainText_13Nov2017.pdf. Accessed 3 Nov 2017
  2. 2.
    Guenin L, Simeone R, Demangel C (2009) Lipids of pathogenic Mycobacteria: contributions to virulence and host immune suppression. Transbound Emerg Dis 56:255–268CrossRefGoogle Scholar
  3. 3.
    Marrakchi H, Laneelle MA, Daffe M (2014) Mycolic acids: structures, biosynthesis, and beyond. Chem Biol 16:67–85CrossRefGoogle Scholar
  4. 4.
    Queiroz A, Riley LW (2017) Bacterial immunostat: Mycobacterium tuberculosis lipids and their role in the host immune response. Rev Soc Bras Med Trop 50(1):9–18CrossRefPubMedGoogle Scholar
  5. 5.
    Takayama K, Wang C, Besra GS (2005) Pathway to synthesis and processing of mycolic acids in Mycobacterium tuberculosis. Clin Microbiol Rev 18(1):81–101CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Sankaranarayanan R, Saxena P, Marathe UB, Gokhale RS, Shanmugam VM, Rukmini RA (2004) Novel tunnel in mycobacterial type III polyketide synthase reveals the structural basis for generating diverse metabolites. Nat Struct Mol Biol 9:894–900CrossRefGoogle Scholar
  7. 7.
    Blunt JW, Copp BR, Keyzers RA, Munro MH, Prinsep MR (2012) Marine natural products. Nat Prod Rep 29:144–222CrossRefPubMedGoogle Scholar
  8. 8.
    Blunt JW, Copp BR, Keyzers RA, Munro MH, Prinsep MR (2015) Marine natural products. Nat Prod Rep 32:116–211CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Molinski TF, Dalisay DS, Lievens SL, Saludes JP (2009) Drug development from marine natural products. Nat Rev Drug Discov 8:69–85CrossRefPubMedGoogle Scholar
  10. 10.
    Felix CR, Gupta R, Geden S, Roberts J, Winder P, Pomponi SA, Diaz MC, Reed JK, Wright AE, Rohde KH (2017) Selective killing of dormant Mycobacterium tuberculosis by marine natural products. Antimicrob Agents Chemother 61(8):e00743–e00717Google Scholar
  11. 11.
    Ancheeva E, El-Neketi M, Daletos G, Ebrahim W, Song W, Lin W, Proksch P (2018) Anti-infective compounds from marine organisms. In: Grand challenges in marine biotechnology. Springer, Cham, pp 97–155CrossRefGoogle Scholar
  12. 12.
    Huang Q, Lu G, Shen HM, Chung MCM, Choon NO (2007) Anti-cancer properties of anthraquinones from rhubarb. Med Res Rev 27(5):609–630CrossRefPubMedGoogle Scholar
  13. 13.
    Sweidan K, Zalloum H, Sabbah DA, Idris G, Abudosh K, Mubarak MS (2018) Synthesis, characterization, and anticancer evaluation of some new N 1-(anthraquinon-2-yl) amidrazone derivatives. Can J Chem 96(12):1123–1128CrossRefGoogle Scholar
  14. 14.
    Khan N, Karodi R, Siddiqui A, Thube S, Rub R (2011) Development of anti-acne gel formulation of anthraquinones rich fraction fromRubia cordifolia (Rubiaceae). Int J Appl Res Nat Prod 4(4):28–36Google Scholar
  15. 15.
    Fiorito S, Epifano F, Taddeo VA, Genovese S (2017) Recent acquisitions on oxyprenylated secondary metabolites as anti-inflammatory agents. Eur J Med Chem 153:116–122CrossRefPubMedGoogle Scholar
  16. 16.
    Davis R, Agnew P, Shapiro E (1986) Antiarthritic activity of anthraquinones found in aloe for podiatric medicine. J Am Podiatr Med Assoc 76(2):61–66CrossRefPubMedGoogle Scholar
  17. 17.
    Wang F, Qiao Y, Niu H, Zhao H (2017) Anti-arthritic effect of total anthraquinones from Polygonum cuspidatum on type II collagen-induced arthritis in rats. Trop J Pharm Res 16(10):2453–2459Google Scholar
  18. 18.
    Wuthi-udomlert M, Kupittayanant P, Gritsanapan W (2010) In vitro evaluation of antifungal activity of anthraquinone derivatives of Senna alata. J Health Res 24(3):117–122Google Scholar
  19. 19.
    Fosso MY, Chan KY, Gregory R, Chang CWT (2012) Library synthesis and antibacterial investigation of cationic anthraquinone analogs. ACS Comb Sci 14(3):231–235CrossRefPubMedGoogle Scholar
  20. 20.
    Barnard DL, Fairbairn DW, O’Neill KL, Gage TL, Sidwell RW (1995) Anti-human cytomegalovirus activity and toxicity of sulfonated anthraquinones and anthraquinone derivatives. Antivir Res 28:317–329CrossRefPubMedGoogle Scholar
  21. 21.
    Jackson TC, Verrier JD, Kochanek PM (2013) Anthraquinone-2-sulfonic acid (AQ2S) is a novel neurotherapeutic agent. Cell Death Dis 4(1):e451CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Kanokmedhakul S, Kanokmedhakul K, Nutchanat P, Soytong K, Kongsaeree P, Suksamrarn A (2002) Antimycobacterial anthraquinone-chromanone compound and diketopiperazine alkaloid from the fungus Chaetomium globosum KMITL-N0802. Planta Med 68:834–836CrossRefPubMedGoogle Scholar
  23. 23.
    Kongkiat T, Nanthaphong K, Vatcharin R, Souwalak P, Sita P, Jariya S (2010) Anthraquinone, cyclopentanone, and naphthoquinone derivatives from the sea fan-derived fungi Fusarium spp. PSU-F14 and PSU-F135. J Nat Prod 73:1507–1511CrossRefGoogle Scholar
  24. 24.
    Mishra SK, Tiwari S, Shrivastava A, Srivastava S, Boudh GK, Chourasia SK (2014) Antidyslipidemic effect and antioxidant activity of anthraquinone derivatives from Rheum emodi rhizomes in dyslipidemic rats. J Nat Med 68:363–371CrossRefPubMedGoogle Scholar
  25. 25.
    Riccardi G, Pasca MR (2014) Trends in discovery of new drugs for tuberculosis therapy. J Antibiot 67:655–659CrossRefPubMedGoogle Scholar
  26. 26.
    Kuni Takayama EL, Armstrong KA, Kunugi, & James OK (1979) Inhibition by ethambutol of mycolic acid transfer into the cell wall of Mycobacterium smegmatis. Antimicrob Agents Chemother 16(2):240–242CrossRefPubMedCentralGoogle Scholar
  27. 27.
    Yamashita S, Furubayashi T, Kataoka M, Sakane T, Sezaki H, Tokuda H (2000) Optimized conditions for prediction of intestinal drug permeability using caco-2 cells. Eur J Pharmacol 10:195–204CrossRefGoogle Scholar
  28. 28.
  29. 29.
    Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS (2009) AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem 30(16):2785–2791CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Baig MH, Ahmad K, Roy S, Ashraf JM, Adil M, Siddiqui MH, Khan S, Kamal MA, Provazník I, Choi I (2016) Computer aided drug design: success and limitations. Curr Pharm Des 22(5):572–581CrossRefPubMedGoogle Scholar
  31. 31.
    Basso LA, Santos DS (2005) Drugs that inhibit mycolic acid biosynthesis in Mycobacterium tuberculosis: an update. Med Chem Rev 2:393–413Google Scholar
  32. 32.
    Denholm JT, McBryde ES, Eisen DP, Penington JS, Chen C, Street AC (2014) Adverse effects of isoniazid preventative therapy for latent tuberculosis infection: a prospective cohort study. Drug Health Patient Saf 6:145–149CrossRefGoogle Scholar
  33. 33.
    Chan RY, Kwok AK (2006) Ocular toxicity of ethambutol. Hong Kong Med J 12(1):56–60PubMedGoogle Scholar
  34. 34.
    Chung-Delgado K, Revilla-Montag A, Guillen-Bravo S, Velez-Segovia E, Soria-Montoya A, Nuñez-Garbin A et al (2011) Factors associated with anti-tuberculosis medication adverse effects: a case–control study in Lima, Peru. PLoS ONE, 6(11), e27610Google Scholar
  35. 35.
    Banerjee A, Sugantino M, Sacchettini JC, Jacobs WR Jr (1998) The mabA gene from the inhA operon of Mycobacterium tuberculosis encodes a 3-ketoacyl reductase that fails to confer isoniazid resistance. Microbiology 144:2697–2707CrossRefPubMedGoogle Scholar
  36. 36.
    Cantaloube S, Veyron-Churlet R, Haddache N, Daffé M, Zerbib D (2011) The Mycobacterium tuberculosis FAS-II dehydratases and methyltransferases define the specificity of the mycolic acid elongation complexes. PLoS ONE 6(12):e29564CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Saxena P, Yadav G, Mohanty D, Gokhale RS (2003) A new family of type III polyketide synthases in Mycobacterium tuberculosis. J Biol Chem 278(45):44780–44790CrossRefPubMedGoogle Scholar
  38. 38.
    Kolattukudy PE, Fernandes ND, Azad AK, Fitzmaurice AM, Sirakova TD (1997) Biochemistry and molecular genetics of cell-wall lipid biosynthesis in mycobacteria. Mol Microbiol 24(2):263–270CrossRefPubMedGoogle Scholar
  39. 39.
    Kavanagh KL, Jornvall H, Persson B, Oppermann U (2008) Medium and short-chain dehydrogenase/reductase gene and protein families: the SDR superfamily: functional and structural diversity within a family of metabolic and regulatory enzymes. Cel Mol Life Sci 65(24):3895–3906CrossRefGoogle Scholar
  40. 40.
    Rosado LA, Caceres RA, de Azevedo Jr WF, Basso LA, Santos DS (2012) Role of serine140 in the mode of action of Mycobacterium tuberculosis beta-ketoacyl-ACP reductase (MabA). BMC Res 5:526CrossRefGoogle Scholar
  41. 41.
    Wang C, Wang J, Huang Y, Chen H, Li Y, Zhong L, Chen Y, Chen S, Wang J, Kang J, Peng Y, Yang B, Lin Y, She Z, Lai X (2013) Anti-mycobacterial activity of marine fungus-derived 4-deoxybostrycin and nigrosporin. Molecules 18:1728–1740CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Sturdy M, Krunic A, Cho S, Franzblau S, Orjala J (2010) Eucapsitrione, an anti-Mycobacterium tuberculosis anthraquinone derivative from the cultured freshwater Cyanobacterium eucapsis sp. J Nat Prod 73(8):1441–1443CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Lijian X, We,i M, Cong C, Jian W, Wenjun S, Qinggui W (2015) Antibacterial and antifungal compounds from marine fungi. Mar Drugs 13:3479–3513CrossRefGoogle Scholar
  44. 44.
    Lee YM, Li H, Hong J, Cho HY, Bae KS, Kim MA, Kim DK, Jung JH (2010) Bioactive metabolites from the sponge-derived fungus Aspergillus versicolor. Arch Pharm Res 33:231–235CrossRefPubMedGoogle Scholar
  45. 45.
    Wu CJ, Li CW, Cui CB (2014) Seven new and two known lipopeptides as well as five known polyketides: the activated production of silent metabolites in a marine-derived fungus by chemical mutagenesis strategy using diethyl sulphate. Mar Drugs 12:1815–1838CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  • Akanksha Sharma
    • 1
  • M Hayatul Islam
    • 1
  • Nida Fatima
    • 1
  • Tarun K. Upadhyay
    • 1
  • M. Kalim A. Khan
    • 2
  • Upendra N. Dwivedi
    • 3
  • Rolee Sharma
    • 1
    Email author
  1. 1.Department of BiosciencesIntegral UniversityLucknowIndia
  2. 2.Department of BioengineeringIntegral UniversityLucknowIndia
  3. 3.Department of Biochemistry, Bioinformatics Infrastructure Facility, Centre of Excellence in BioinformaticsUniversity of LucknowLucknowIndia

Personalised recommendations