Original Article

Effect of Metabolite Extract of Streptomyces hygroscopicus subsp. hygroscopicus on Plasmodium falciparum 3D7 in Vitro

Abstract

Background: Malaria eradication has been complicated by the repeated emergence of antimalarial drug resistances. We aimed to determine whether a metabolite extract of Streptomyces hygrocopicus subsp. hygroscopicus could decrease the viability of Plasmodium falciparum 3D7 in vitro.

Methods: S. hygroscopicus subsp. hygroscopicus isolates were inoculated and fermented on the ISP4 medium. The fermented S. hygroscopicus was mixed with ethylacetate 1:5 (v/v), and the solvent phase was evaporated. Several concentrations of isolated extract was added to the P. falciparum 3D7 culture containing trophozoite and schizont stages in 24 wells plates when the degree of parasite-infected erythrocytes reached 5%, then incubated for 8 hours. DNA parasite density was measured using flow cytometry, parasite degree and morphology were observed under microscopic by Giemsa-stained smears. 

Results: The metabolite extract affected the morphology of almost all of parasite asexual stages. Schizonts and trophozoites failed to grow and appeared damaged with pycnotic cores and loss of cytoplasmic content. At 8 hours there was a significant decrease in DNA parasite density in culture exposed to 2.6 mg/ml and 13 mg/ml (P = 0.002; P = 0.024) of the extract. The degree of parasite-infected erythrocytes was decreased from the beginning of exposure (0.02 mg/ml of the extract). There was a significant inverse correlation between the concentration of extract and the degree of parasite-infected erythrocytes as well as the density of DNA parasite (r = -0.772, P = 0.000; r =-0.753; P =0.000).

Conclusion: Metabolite extract of S. hygroscopicus subsp. hygroscopicus causes morphological damage, decreases the degree of parasite-infected erythrocytes and the DNA density of P. falciparum 3D7 in vitro.

Klein EY. Antimalarial drug resistance: a review of the biology and strategies to delay emergence and spread. Int J Antimicrob Agents [Internet]. 2013 Apr 8;41(4):311–7. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3610176/

Ciechanover A. Proteolysis: from the lysosome to ubiquitin and the proteasome. Nat Rev Mol Cell Biol [Internet]. 2005 Jan;6(1):79–87. Available from: http://dx.doi.org/10.1038/nrm1552

Horrocks P, Newbold CI. Intraerythrocytic polyubiquitin expression in Plasmodium falciparum is subjected to developmental and heat-hock control. Mol Biochem Parasitol [Internet]. 2000 Jan 5;105(1):115–25. Available from: http://www.sciencedirect.com/science/article/pii/S0166685199001747

Oakley MSM, Kumar S, Anantharaman V, Zheng H, Mahajan B, Haynes JD, et al. Molecular Factors and Biochemical Pathways Induced by Febrile Temperature in Intraerythrocytic Plasmodium falciparum Parasites . Infect Immun [Internet]. 2007 Apr 5;75(4):2012–25. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1865691/

Kreidenweiss A, Kremsner PG, Mordmüller B. Comprehensive study of proteasome inhibitors against Plasmodium falciparum laboratory strains and field isolates from Gabon. Malar J. 2008;7:187.

de Lima Procópio RE, da Silva IR, Martins MK, de Azevedo JL, de Araújo JM. Antibiotics produced by Streptomyces. Brazilian J Infect Dis [Internet]. 2012;16(5):466–71. Available from: http://dx.doi.org/10.1016/j.bjid.2012.08.014

Sugawara K, Hatori M, Nishiyama Y, Tomita K, Kamei H, Konishi M, et al. Eponemycin, a new antibiotic active against B16 melanoma. I. Production, isolation, structure and biological activity. J Antibiot (Tokyo). 1990;43(1):8–18.

Meng L, Kwok BHB, Sin N, Crews CM. Eponemycin Exerts Its Antitumor Effect through the Inhibition of Proteasome Function. Cancer Res [Internet]. 1999 Jun 1;59(12):2798 LP-2801. Available from: http://cancerres.aacrjournals.org/content/59/12/2798.abstract

Reynolds JM, El Bissati K, Brandenburg J, Günzl A, Mamoun C Ben. Antimalarial activity of the anticancer and proteasome inhibitor bortezomib and its analog ZL(3)B. BMC Clin Pharmacol [Internet]. 2007 Oct 23;7:13. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2213633/

Czesny B, Goshu S, Cook JL, Williamson KC. The Proteasome Inhibitor Epoxomicin Has Potent Plasmodium falciparum Gametocytocidal Activity . Antimicrob Agents Chemother [Internet]. 2009 Oct 3;53(10):4080–5. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2764187/

Shepherd MD, Kharel MK, Bosserman MA, Rohr J. Laboratory Maintenance of Streptomyces species. Curr Protoc Microbiol [Internet]. 2010 Aug;CHAPTER:Unit-10E.1. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2950629/

Sharma H, Parihar L. Antifungal activity of extracts obtained from actinomycetes. J Yeast Fungal Res. 2010;1(10):197–200.

Rivo YB, Alkarimah A, Ramadhani NN, Cahyono AW, Laksmi DA, Winarsih S, et al. Metabolite extract of Streptomyces hygroscopicus Hygroscopicus inhibit the growth of Plasmodium berghei through inhibition of ubiquitin - Proteasome system. Trop Biomed. 2013;30(2):291–300.

Moll K, Ljungström I, Perlmann H, Scherf A, Wahlgren M. Ethods in. Life Sci. 2008;1–9.

Kisselev AF, van der Linden WA, Overkleeft HS. Proteasome Inhibitors: An Expanding Army Attacking a Unique Target. Chem Biol [Internet]. 2012 Jan 27;19(1):99–115. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3503453/

Kramer HB, Nicholson B, Kessler BM, Altun M. Detection of ubiquitin–proteasome enzymatic activities in cells: Application of activity-based probes to inhibitor development. Biochim Biophys Acta - Mol Cell Res [Internet]. 2012 Nov;1823(11):2029–37. Available from: http://www.sciencedirect.com/science/article/pii/S0167488912001309

Sinha A, Sarkar S. Ubiquitin-Proteasome System- a target to control pathogenic protozoa. Formatex. 2013;764–73.

Paugam A, Bulteau A-L, Dupouy-Camet J, Creuzet C, Friguet B. Characterization and role of protozoan parasite proteasomes. Trends Parasitol [Internet]. 2016 Oct 28;19(2):55–9. Available from: http://dx.doi.org/10.1016/S1471-4922(02)00064-8

Aminake MN, Arndt HD, Pradel G. The proteasome of malaria parasites: A multi-stage drug target for chemotherapeutic intervention? Int J Parasitol Drugs Drug Resist [Internet]. 2012;2:1–10. Available from: http://dx.doi.org/10.1016/j.ijpddr.2011.12.001

Kim KB, Myung J, Sin N, Crews CM. Proteasome inhibition by the natural products epoxomicin and dihydroeponemycin: Insights into specificity and potency. Bioorg Med Chem Lett [Internet]. 1999 Dec 6;9(23):3335–40. Available from: http://www.sciencedirect.com/science/article/pii/S0960894X99006125

Delcros JG, Floc MB, Prigent C, Arlot-bonnemains Y. Proteasome Inhibitors as Therapeutic Agents : Current and Future Strategies. Curr Med Chem. 2003;10(6):479–503.

Xolalpa W, Perez-Galan P, Roue MSR and G. Targeting the Ubiquitin Proteasome System: Beyond Proteasome Inhibition [Internet]. Vol. 19, Current Pharmaceutical Design. 2013. p. 4053–93. Available from: http://www.eurekaselect.com/node/109906/article

Kim KB, Fonseca FN, Crews CM. Development and Characterization of Proteasome Inhibitors. Methods Enzymol [Internet]. 2005;399:585–609. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2556561/

Mitra P, Deshmukh AS, Dhar SK. DNA replication during intra-erythrocytic stages of human malarial parasite Plasmodium falciparum. Curr Sci. 2012;102(5):725–40.

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IssueVol 14 No 3 (2019) QRcode
SectionOriginal Article(s)
DOI https://doi.org/10.18502/ijpa.v14i3.1484
Keywords
Streptomyces hygroscopicus subsp. hygroscopicus Plasmodium falciparum 3D7 DNA parasite density

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How to Cite
1.
FITRI LE, ALKARIMAH A, CAHYONO AW, LADY WN, ENDHARTI AT, NUGRAHA RYB. Effect of Metabolite Extract of Streptomyces hygroscopicus subsp. hygroscopicus on Plasmodium falciparum 3D7 in Vitro. Iran J Parasitol. 2019;14(3):444-452.