Anti-malarial Activities of Two Soil Actinomycete Isolates from Sabah via Inhibition of Glycogen Synthase Kinase 3β.
Exploiting natural resources for bioactive compounds is an attractive drug discovery strategy in search for new anti-malarial drugs with novel modes of action. Initial screening efforts in our laboratory revealed two preparations of soil-derived actinomycetes (H11809 and FH025) with potent anti-malarial activities. Both crude extracts showed glycogen synthase kinase 3β (GSK3β)-inhibitory activities in a yeast-based kinase assay. We have previously shown that the GSK3 inhibitor, lithium chloride (LiCl), was able to suppress parasitaemia development in a rodent model of malarial infection. The present study aims to evaluate whether anti-malarial activities of H11809 and FH025 involve the inhibition of GSK3β. The acetone crude extracts of H11809 and FH025 each exerted strong inhibition on the growth of Plasmodium falciparum 3D7 in vitro with 50% inhibitory concentration (IC50) values of 0.57 ± 0.09 and 1.28 ± 0.11 µg/mL, respectively. The tested extracts exhibited Selectivity Index (SI) values exceeding 10 for the 3D7 strain. Both H11809 and FH025 showed dosage-dependent chemo-suppressive activities in vivo and improved animal survivability compared to non-treated infected mice. Western analysis revealed increased phosphorylation of serine (Ser 9) GSK3β (by 6.79 to 6.83-fold) in liver samples from infected mice treated with H11809 or FH025 compared to samples from non-infected or non-treated infected mice. A compound already identified in H11809 (data not shown), dibutyl phthalate (DBP) showed active anti-plasmodial activity against 3D7 (IC50 4.87 ± 1.26 µg/mL which is equivalent to 17.50 µM) and good chemo-suppressive activity in vivo (60.80% chemo-suppression at 300 mg/kg body weight [bw] dosage). DBP administration also resulted in increased phosphorylation of Ser 9 GSK3β compared to controls. Findings from the present study demonstrate that the potent anti-malarial activities of H11809 and FH025 were mediated via inhibition of host GSK3β. In addition, our study suggests that DBP is in part the bioactive component contributing to the anti-malarial activity displayed by H11809 acting through the inhibition of GSK3β.
School of Biosciences and Biotechnology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600 UKM, Bangi, Selangor, Malaysia.
Dhiana Efani
DE
Dahari
School of Biosciences and Biotechnology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600 UKM, Bangi, Selangor, Malaysia.
Raifana Mohamad
RM
Salleh
School of Science and Technology, Universiti Malaysia Sabah, 88999 Kota Kinabalu, Sabah, Malaysia.
Fauze
F
Mahmud
School of Science and Technology, Universiti Malaysia Sabah, 88999 Kota Kinabalu, Sabah, Malaysia.
Lee Ping
LP
Chin
School of Biosciences and Biotechnology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600 UKM, Bangi, Selangor, Malaysia.
Noor
N
Embi
School of Biosciences and Biotechnology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600 UKM, Bangi, Selangor, Malaysia.
Hasidah Mohd
HM
Sidek
Actinomycete; Anti-malarial; Dibutyl Phthalate; GSK3β
Mol Cell Biol. 2000 Sep;20(18):6712-20
10958669
Ann Trop Med Parasitol. 1975 Jun;69(2):155-71
1098584
Braz J Med Biol Res. 2003 Nov;36(11):1465-9
14576900
Biochim Biophys Acta. 2004 Mar 11;1697(1-2):181-96
15023360
J Ethnopharmacol. 2006 Jan 16;103(2):236-40
16171960
Curr Drug Targets. 2006 Nov;7(11):1377-88
17100578
Methods Mol Biol. 2007;362:385-9
17417026
Clin Infect Dis. 2008 Jan 15;46(2):165-71
18171245
PLoS One. 2008 Jun 04;3(6):e2335
18523554
J Nat Prod. 2009 Aug;72(8):1520-3
19711989
Malar J. 2010 May 12;9:124
20462416
Malar J. 2011 Feb 02;10:20
21288335
Trop Biomed. 2010 Dec;27(3):624-31
21399604
Int J Alzheimers Dis. 2012;2012:381029
22888461
Aquat Toxicol. 2012 Nov 15;124-125:188-96
22975441
Trop Biomed. 2013 Jun;30(2):291-300
23959495
Trends Microbiol. 2014 Apr;22(4):208-17
24618402
PLoS One. 2014 Mar 11;9(3):e90972
24618707
Mar Drugs. 2014 May 02;12(5):2590-613
24798926
Molecules. 2014 Sep 23;19(9):15237-57
25251193
J Biol Chem. 2015 Jan 23;290(4):2321-33
25477508
Biochim Biophys Acta. 2015 Oct;1854(10 Pt B):1644-9
25861860
Front Mar Sci. 2014 Oct;1:
27785452
Nature. 1970 Aug 15;227(5259):680-5
5432063
Eur J Biochem. 1980 Jun;107(2):519-27
6249596
J Immunol Methods. 1983 Dec 16;65(1-2):55-63
6606682
Science. 1976 Aug 20;193(4254):673-5
781840
Am J Trop Med Hyg. 1993 Feb;48(2):205-10
8447524
Anal Biochem. 1976 May 7;72:248-54
942051