In vivo experiments demonstrate the potent antileishmanial efficacy of repurposed suramin in visceral leishmaniasis.
Animals
Antiprotozoal Agents
/ pharmacology
Apoptosis
/ drug effects
Cytokines
/ metabolism
Disease Models, Animal
Dose-Response Relationship, Drug
Inhibitory Concentration 50
Leishmania donovani
/ drug effects
Leishmaniasis, Visceral
/ drug therapy
Membrane Potential, Mitochondrial
/ drug effects
Mice
Mice, Inbred BALB C
Nitric Oxide
/ metabolism
Phosphoglycerate Kinase
/ drug effects
RAW 264.7 Cells
/ drug effects
Reactive Oxygen Species
/ metabolism
Suramin
/ pharmacology
Journal
PLoS neglected tropical diseases
ISSN: 1935-2735
Titre abrégé: PLoS Negl Trop Dis
Pays: United States
ID NLM: 101291488
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
19
11
2019
accepted:
07
07
2020
revised:
15
09
2020
pubmed:
1
9
2020
medline:
6
10
2020
entrez:
1
9
2020
Statut:
epublish
Résumé
Treatment failure and resistance to the commonly used drugs remains a major obstacle for successful chemotherapy against visceral leishmaniasis (VL). Since the development of novel therapeutics involves exorbitant costs, the effectiveness of the currently available antitrypanosomatid drug suramin has been investigated as an antileishmanial, specifically for VL,in vitro and in animal model experiments. Leishmania donovani promastigotes were treated with suramin and studies were performed to determine the extent and mode of cell mortality, cell cycle arrest and other in vitro parameters. In addition, L. donovani infected BALB/c mice were administered suramin and a host of immunological parameters determined to estimate the antileishmanial potency of the drug. Finally, isothermal titration calorimetry (ITC) and enzymatic assays were used to probe the interaction of the drug with one of its putative targets namely parasitic phosphoglycerate kinase (LmPGK). The in vitro studies revealed the potential efficacy of suramin against the Leishmania parasite. This observation was further substantiated in the in vivo murine model, which demonstrated that upon suramin administration, the Leishmania infected BALB/c mice were able to reduce the parasitic burden and also generate the host protective immunological responses. ITC and enzyme assays confirmed the binding and consequent inhibition of LmPGK due to the drug. All experiments affirmed the efficacy of suramin against L. donovani infection, which could possibly lead to its inclusion in the repertoire of drugs against VL.
Sections du résumé
BACKGROUND
Treatment failure and resistance to the commonly used drugs remains a major obstacle for successful chemotherapy against visceral leishmaniasis (VL). Since the development of novel therapeutics involves exorbitant costs, the effectiveness of the currently available antitrypanosomatid drug suramin has been investigated as an antileishmanial, specifically for VL,in vitro and in animal model experiments.
METHODOLOGY/PRINCIPAL
Leishmania donovani promastigotes were treated with suramin and studies were performed to determine the extent and mode of cell mortality, cell cycle arrest and other in vitro parameters. In addition, L. donovani infected BALB/c mice were administered suramin and a host of immunological parameters determined to estimate the antileishmanial potency of the drug. Finally, isothermal titration calorimetry (ITC) and enzymatic assays were used to probe the interaction of the drug with one of its putative targets namely parasitic phosphoglycerate kinase (LmPGK).
FINDINGS
The in vitro studies revealed the potential efficacy of suramin against the Leishmania parasite. This observation was further substantiated in the in vivo murine model, which demonstrated that upon suramin administration, the Leishmania infected BALB/c mice were able to reduce the parasitic burden and also generate the host protective immunological responses. ITC and enzyme assays confirmed the binding and consequent inhibition of LmPGK due to the drug.
CONCLUSIONS/SIGNIFICANCE
All experiments affirmed the efficacy of suramin against L. donovani infection, which could possibly lead to its inclusion in the repertoire of drugs against VL.
Identifiants
pubmed: 32866156
doi: 10.1371/journal.pntd.0008575
pii: PNTD-D-19-01975
pmc: PMC7491717
doi:
Substances chimiques
Antiprotozoal Agents
0
Cytokines
0
Reactive Oxygen Species
0
Nitric Oxide
31C4KY9ESH
Suramin
6032D45BEM
Phosphoglycerate Kinase
EC 2.7.2.3
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0008575Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
Références
J Enzyme Inhib Med Chem. 2019 Dec;34(1):1100-1109
pubmed: 31124384
Acta Trop. 2008 Apr;106(1):72-4
pubmed: 18329619
PLoS One. 2017 Feb 7;12(2):e0171306
pubmed: 28170432
Exp Parasitol. 2006 Nov;114(3):204-14
pubmed: 16707127
Antimicrob Agents Chemother. 2012 Feb;56(2):1031-41
pubmed: 22123699
Trends Parasitol. 2006 Dec;22(12):552-7
pubmed: 17023215
Biomed Res Int. 2018 Jul 10;2018:9872095
pubmed: 30105272
Eur J Biochem. 1984 Nov 2;144(3):475-83
pubmed: 6489338
BMC Res Notes. 2018 May 21;11(1):319
pubmed: 29784022
Antiviral Res. 2015 Sep;121:39-46
pubmed: 26112648
J Parasit Dis. 2011 Oct;35(2):116-22
pubmed: 23024491
Antimicrob Agents Chemother. 2015 Oct;59(10):5999-6006
pubmed: 26169419
Pathog Glob Health. 2013 Jul;107(5):242-52
pubmed: 23916333
Mini Rev Med Chem. 2008 Nov;8(13):1384-94
pubmed: 18991754
J Bacteriol. 1992 Oct;174(19):6076-86
pubmed: 1400158
Methods Enzymol. 1994;233:338-46
pubmed: 8015468
Eur J Biochem. 1987 Feb 2;162(3):493-500
pubmed: 3830152
FEMS Immunol Med Microbiol. 2007 Nov;51(2):229-42
pubmed: 17714488
J Biol Chem. 2011 Sep 9;286(36):31232-40
pubmed: 21733839
Biochem Pharmacol. 2004 Sep 15;68(6):1033-40
pubmed: 15313398
J Infect Dis. 2011 Oct 1;204(7):1134-7
pubmed: 21881130
J Parasit Dis. 2016 Jun;40(2):436-43
pubmed: 27413317
Sci Rep. 2017 Sep 4;7(1):10330
pubmed: 28871097
Antimicrob Agents Chemother. 1994 Mar;38(3):563-9
pubmed: 8203855
Indian J Med Res. 2006 Mar;123(3):295-310
pubmed: 16778312
EMBO Mol Med. 2012 Oct;4(10):1126-43
pubmed: 23027614
Pharmacol Rev. 1993 Jun;45(2):177-203
pubmed: 8396782
Mol Biochem Parasitol. 1993 Jun;59(2):201-10
pubmed: 8341319
Parasitol Res. 2012 Jul;111(1):361-9
pubmed: 22437790
J Glob Infect Dis. 2010 May;2(2):151-8
pubmed: 20606971
Pharm Biol. 2017 Dec;55(1):998-1009
pubmed: 28173714
Antimicrob Agents Chemother. 2010 Dec;54(12):5344-51
pubmed: 20837758
Emerg Microbes Infect. 2014 Sep;3(9):e62
pubmed: 26038755
Clin Dev Immunol. 2012;2012:925135
pubmed: 22474485
Acta Trop. 2016 Dec;164:177-184
pubmed: 27629023
Front Cell Infect Microbiol. 2012 Jun 12;2:83
pubmed: 22919674
Virol J. 2016 Aug 31;13:149
pubmed: 27581733
PLoS Negl Trop Dis. 2012;6(12):e1987
pubmed: 23301108
Bioorg Med Chem. 2009 Jun 1;17(11):3900-8
pubmed: 19428261
PLoS One. 2014 Apr 14;9(4):e94596
pubmed: 24732039
Exp Parasitol. 2012 Jan;130(1):39-47
pubmed: 22019416
J Immunol. 2005 Jun 1;174(11):7160-71
pubmed: 15905560
Annu Rev Immunol. 1989;7:145-73
pubmed: 2523712
Cancer Cell Int. 2015 May 13;15:52
pubmed: 26052253
J Immunol. 2009 Jul 1;183(1):470-9
pubmed: 19542458
Br J Pharmacol. 2007 Dec;152(8):1155-71
pubmed: 17618313
Int J Nanomedicine. 2017 Mar 20;12:2189-2204
pubmed: 28356736
Cancer Res. 2005 Jan 15;65(2):613-21
pubmed: 15695406