1921
Volume 94, Issue 2
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645

Abstract

Abstract

Leishmaniasis is a complex tropical disease caused by kinetoplastid parasitic protozoa of the genus and is transmitted by the sand fly insect vector. Cutaneous leishmaniasis (CL) is the most common form of this disease, and CL infections often result in serious skin lesions and scars. CL remains a public health problem in many endemic countries worldwide because of the absence of effective, safe, and cost-effective drugs for treatment. One of the strategies we chose to use to find novel chemical entities worthy of further development as antileishmanials involved screening synthetic and natural products libraries. In our study, we developed a intracellular amastigote assay that uses the activity of luciferase as a measure of parasite proliferation and used this assay to screen a collection of 400 compounds obtained from Medicines for Malaria Venture (MMV) for their antileishmanial activity. Our results showed that 14 compounds identified by MMV as antimalarial drugs have antileishmanial activity and can potentially be optimized for CL drug development.

[open-access] This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Loading

Article metrics loading...

/content/journals/10.4269/ajtmh.15-0448
2016-02-03
2017-11-19
Loading full text...

Full text loading...

/deliver/fulltext/14761645/94/2/340.html?itemId=/content/journals/10.4269/ajtmh.15-0448&mimeType=html&fmt=ahah

References

  1. World Health Organization, 2010. Control of the leishmaniases. World Health Organ Tech Rep Ser 949: 1186.
  2. Croft SL, Coombs GH, , 2003. Leishmaniasis—current chemotherapy and recent advances in the search for novel drugs. Trends Parasitol 19: 502508.[Crossref]
  3. Dowlati Y, , 1996. Cutaneous leishmaniasis: clinical aspect. Clin Dermatol 14: 425431.[Crossref]
  4. Grogl M, Hickman M, Ellis W, Hudson T, Lazo JS, Sharlow ER, Johnson J, Berman J, Sciotti RJ, , 2013. Review: drug discovery algorithm for cutaneous leishmaniasis. Am J Trop Med Hyg 88: 216221.[Crossref]
  5. Corrales RM, Sereno D, Mathieu-Daude F, , 2010. Deciphering the Leishmania exoproteome: what we know and what we can learn. FEMS Immunol Med Microbiol 58: 2738.[Crossref]
  6. Mandal S, Moudgil M, Mandal SK, , 2009. Rational drug design. Eur J Pharmacol 625: 90100.[Crossref]
  7. Ioset JR, , 2008. Natural products for neglected diseases: a review. Curr Org Chem 12: 643666.[Crossref]
  8. Gilbert IH, , 2013. Drug discovery for neglected diseases: molecular target-based and phenotypic approaches. J Med Chem 56: 77197726.[Crossref]
  9. Gamo FJ, Sanz LM, Vidal J, de Cozar C, Alvarez E, Lavandera JL, Vanderwall DE, Green DV, Kumar V, Hasan S, Brown JR, Peishoff CE, Cardon LR, Garcia-Bustos JF, , 2010. Thousands of chemical starting points for antimalarial lead identification. Nature 465: 305310.[Crossref]
  10. Guiguemde WA, Shelat AA, Bouck D, Duffy S, Crowther GJ, Davis PH, Smithson DC, Connelly M, Clark J, Zhu F, Jimenez-Diaz MB, Martinez MS, Wilson EB, Tripathi AK, Gut J, Sharlow ER, Bathurst I, El Mazouni F, Fowble JW, Forquer I, McGinley PL, Castro S, Angulo-Barturen I, Ferrer S, Rosenthal PJ, Derisi JL, Sullivan DJ, Lazo JS, Roos DS, Riscoe MK, Phillips MA, Rathod PK, Van Voorhis WC, Avery VM, Guy RK, , 2010. Chemical genetics of Plasmodium falciparum . Nature 465: 311315.[Crossref]
  11. Meister S, Plouffe DM, Kuhen KL, Bonamy GM, Wu T, Barnes SW, Bopp SE, Borboa R, Bright AT, Che J, Cohen S, Dharia NV, Gagaring K, Gettayacamin M, Gordon P, Groessl T, Kato N, Lee MC, McNamara CW, Fidock DA, Nagle A, Nam TG, Richmond W, Roland J, Rottmann M, Zhou B, Froissard P, Glynne RJ, Mazier D, Sattabongkot J, Schultz PG, Tuntland T, Walker JR, Zhou Y, Chatterjee A, Diagana TT, Winzeler EA, , 2011. Imaging of Plasmodium liver stages to drive next-generation antimalarial drug discovery. Science 334: 13721377.[Crossref]
  12. Spangenberg T, Burrows JN, Kowalczyk P, McDonald S, Wells TN, Willis P, , 2013. The open access malaria box: a drug discovery catalyst for neglected diseases. PLoS One 8: e62906.[Crossref]
  13. Kaiser M, Maes L, Tadoori LP, Spangenberg T, Ioset JR, , 2015. Repurposing of the open access malaria box for kinetoplastid diseases identifies novel active scaffolds against trypanosomatids. J Biomol Screen 20: 634645.[Crossref]
  14. Buckner FS, Wilson AJ, , 2005. Colorimetric assay for screening compounds against Leishmania amastigotes grown in macrophages. Am J Trop Med Hyg 72: 600605.
  15. Monte-Alegre A, Ouaissi A, Sereno D, , 2006. Leishmania amastigotes as targets for drug screening. Kinetoplastid Biol Dis 5: 6.[Crossref]
  16. De Muylder G, Ang KK, Chen S, Arkin MR, Engel JC, McKerrow JH, , 2011. A screen against Leishmania intracellular amastigotes: comparison to a promastigote screen and identification of a host cell-specific hit. PLoS Negl Trop Dis 5: e1253.[Crossref]
  17. De Rycker M, Hallyburton I, Thomas J, Campbell L, Wyllie S, Joshi D, Cameron S, Gilbert IH, Wyatt PG, Frearson JA, Fairlamb AH, Gray DW, , 2013. Comparison of a high-throughput high-content intracellular Leishmania donovani assay with an axenic amastigote assay. Antimicrob Agents Chemother 57: 29132922.[Crossref]
  18. Siqueira-Neto JL, Moon S, Jang J, Yang G, Lee C, Moon HK, Chatelain E, Genovesio A, Cechetto J, Freitas-Junior LH, , 2012. An image-based high-content screening assay for compounds targeting intracellular Leishmania donovani amastigotes in human macrophages. PLoS Negl Trop Dis 6: e1671.[Crossref]
  19. Bates PA, , 1993. Axenic culture of Leishmania amastigotes. Parasitol Today 9: 143146.[Crossref]
  20. Callahan HL, Portal AC, Devereaux R, Grogl M, , 1997. An axenic amastigote system for drug screening. Antimicrob Agents Chemother 41: 818822.
  21. Teixeira MC, de Jesus Santos R, Sampaio RB, Pontes-de-Carvalho L, dos-Santos WL, , 2002. A simple and reproducible method to obtain large numbers of axenic amastigotes of different Leishmania species. Parasitol Res 88: 963968.[Crossref]
  22. Holzer TR, McMaster WR, Forney JD, , 2006. Expression profiling by whole-genome interspecies microarray hybridization reveals differential gene expression in procyclic promastigotes, lesion-derived amastigotes, and axenic amastigotes in Leishmania mexicana . Mol Biochem Parasitol 146: 198218.[Crossref]
  23. Li Q, Zhao Y, Ni B, Yao C, Zhou Y, Xu W, Wang Z, Qiao Z, , 2008. Comparison of the expression profiles of promastigotes and axenic amastigotes in Leishmania donovani using serial analysis of gene expression. Parasitol Res 103: 821828.[Crossref]
  24. Vermeersch M, da Luz RI, Tote K, Timmermans JP, Cos P, Maes L, , 2009. In vitro susceptibilities of Leishmania donovani promastigote and amastigote stages to antileishmanial reference drugs: practical relevance of stage-specific differences. Antimicrob Agents Chemother 53: 38553859.[Crossref]
  25. Lang T, Goyard S, Lebastard M, Milon G, , 2005. Bioluminescent Leishmania expressing luciferase for rapid and high throughput screening of drugs acting on amastigote-harbouring macrophages and for quantitative real-time monitoring of parasitism features in living mice. Cell Microbiol 7: 383392.[Crossref]
  26. Mandal S, Maharjan M, Ganguly S, Chatterjee M, Singh S, Buckner FS, Madhubala R, , 2009. High-throughput screening of amastigotes of Leishmania donovani clinical isolates against drugs using a colorimetric beta-lactamase assay. Indian J Exp Biol 47: 475479.
  27. Lecoeur H, Buffet P, Morizot G, Goyard S, Guigon G, Milon G, Lang T, , 2007. Optimization of topical therapy for Leishmania major localized cutaneous leishmaniasis using a reliable C57BL/6 model. PLoS Negl Trop Dis 1: e34.[Crossref]
  28. Zhang JH, Chung TD, Oldenburg KR, , 1999. A simple statistical parameter for use in evaluation and validation of high throughput screening assays. J Biomol Screen 4: 6773.[Crossref]
  29. Ferrari M, Fornasiero MC, Isetta AM, , 1990. MTT colorimetric assay for testing macrophage cytotoxic activity in vitro. J Immunol Methods 131: 165172.[Crossref]
  30. Clemons P, Tolliday N, Wagner B, , 2009. Cell-Based Assays for High-Throughput Screening. Cambridge, MA: Humana Press.[Crossref]
  31. Croft SL, Yardley V, Kendrick H, , 2002. Drug sensitivity of Leishmania species: some unresolved problems. Trans R Soc Trop Med Hyg 96 (Suppl 1): S127S129.[Crossref]
  32. Escobar P, Matu S, Marques C, Croft SL, , 2002. Sensitivities of Leishmania species to hexadecylphosphocholine (miltefosine), ET-18-OCH3 (edelfosine) and amphotericin B. Acta Trop 81: 151157.[Crossref]
  33. Garnier T, Brown MB, Lawrence MJ, Croft SL, , 2006. In-vitro and in-vivo studies on a topical formulation of sitamaquine dihydrochloride for cutaneous leishmaniasis. J Pharm Pharmacol 58: 10431054.[Crossref]
  34. Sereno D, Lemesre JL, , 1997. In vitro life cycle of pentamidine-resistant amastigotes: stability of the chemoresistant phenotypes is dependent on the level of resistance induced. Antimicrob Agents Chemother 41: 18981903.
  35. Yardley V, Croft SL, , 1997. Activity of liposomal amphotericin B against experimental cutaneous leishmaniasis. Antimicrob Agents Chemother 41: 752756.
  36. Properties were calculated using SARvision software (Version 3.3). Available at: http://www.schrodinger.com.
  37. Bursavich MG, Clemens JJ, Gilbert AM, How DB, Khafizova G, Laakso LM, Lombardi S, Sabatini JJ, Sum PE, , 2008. 8-hydroxyquinoline compounds and methods thereof. U.S. Patent (WO 2008024922 A3), filed August 23, 2007.
  38. Coombs GS, Schmitt AA, Canning CA, Alok A, Low IC, Banerjee N, Kaur S, Utomo V, Jones CM, Pervaiz S, Toone EJ, Virshup DM, , 2012. Modulation of Wnt/β-catenin signaling and proliferation by a ferrous iron chelator with therapeutic efficacy in genetically engineered mouse models of cancer. Oncogene 31: 213225.[Crossref]
  39. Virshup DM, Coombs G, Banerjee N, Ireland C, , 2010. Methods of treatment using wnt inhibitors. U.S. Patent (WO 2010014948 A1), filed July 31, 2009.
  40. Spooner N, Lad R, Barfield M, , 2009. Dried blood spots as a sample collection technique for the determination of pharmacokinetics in clinical studies: considerations for the validation of a quantitative bioanalytical method. Anal Chem 81: 15571563.[Crossref]
http://instance.metastore.ingenta.com/content/journals/10.4269/ajtmh.15-0448
Loading
/content/journals/10.4269/ajtmh.15-0448
Loading

Data & Media loading...

  • Received : 18 Jun 2015
  • Accepted : 11 Sep 2015

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error