Advertisement

Acta Parasitologica

, Volume 62, Issue 3, pp 582–588 | Cite as

In vitro effects of purine and pyrimidine analogues on Leishmania donovani and Leishmania infantum promastigotes and intracellular amastigotes

  • Samira Azzouz
  • Philippe LawtonEmail author
Article

Abstract

Inhibition of parasite metabolic pathways is a rationale for new chemotherapeutic strategies. The pyrimidine and purine salvage pathways are thus targets against Leishmania donovani and L. infantum, causative agents of visceral human leishmaniasis and canine leishmaniosis. The antiproliferative effect of the pyrimidine analogues Cytarabine and 5-fluorouracil and of the purine analogues Azathioprine and 6-mercaptopurine was evaluated in vitro on the promastigote and the intracellular amastigote stages of the parasite. Cytarabine and 5-fluorouracil were the best inhibitors against promastigotes, whereas 5- fluorouracil and azathioprine displayed the best efficacy against the amastigote stage. The ultrastructural study showed an important cytoplasmic vacuolization and with azathioprine and 5-fluorouracyl, a mitochondrial swelling and appearance of autophagosome-like structures. Alterations of the kinetoplast were also observed with 5-fluorouracil, all these damages eventually resulting in an autolysis process that triggered the subsequent death of the intracellular parasites.

Keywords

L. donovani L. infantum purine analogues pyrimidine analogues antiproliferative effect ultrastructural modifications 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Balasegaram M., Ritmeijer K., Lima M.A., Burza S., Ortiz Genovese G., Milani B., et al. 2012. Liposomal amphotericin B as a treatment for human leishmaniasis. Expert Opinion on Emerging Drugs, 17, 493–510. DOI: 10.1517/14728214.2012.748036CrossRefGoogle Scholar
  2. Carter N.S., Yates P.A., Gessford S.K., Galagan S.R., Landfear S.M., Ullman B. 2010. Adaptive responses to purine starvation in Leishmania donovani. Molecular Microbiology, 78, 92–107. DOI: 10.1111/j.1365-2958.2010.07327.xPubMedPubMedCentralGoogle Scholar
  3. Croft S.L., Olliaro P. 2011. Leishmaniasis chemotherapy–challenges and opportunities. Clinical Microbiology and Infection, 17, 1478–1483. DOI: 10.1111/j.1469-0691.2011.03630.xCrossRefGoogle Scholar
  4. Croft S.L., Sundar S., Fairlamb A.H. 2006. Drug resistance in leishmaniasis. Clinical Microbiological Reviews, 19, 111–126. DOI: 10.1128/CMR.19.1.111-126.2006CrossRefGoogle Scholar
  5. De Koning H.P., Bridges D.J., Burchmore R.J.S. 2005. Purine and pyrimidine transport in pathogenic protozoa: from biology to therapy. FEMS Microbiology Reviews, 29, 987–1020. DOI: 10.1016/j.femsre.2005.03.004CrossRefGoogle Scholar
  6. Dorlo T.P.C., Balasegaram M., Beijnen J.H., de Vries P.J., 2012. Miltefosine: a review of its pharmacology and therapeutic efficacy in the treatment of leishmaniasis. Journal of Antimicrobial Chemotherapy, 67, 2576–2597. DOI: 10.1093/jac/dks275CrossRefGoogle Scholar
  7. Eklund B.I., Moberg M., Bergquist J., Mannervik B. 2006. Divergent activities of human glutathione transferases in the bioactivation of azathioprine. Molecular Pharmacology, 70, 747–754. DOI: 10.1124/mol.106.025288CrossRefGoogle Scholar
  8. Farca A.M., Miniscalco B., Badino P. Odore R., Monticelli P., Trisciu oglio A., Ferroglio E. 2012. Canine leishmaniosis: in vitro efficacy of miltefosine and marbofloxacin alone or in combination with allopurinol against clinical strains of Leishmania infantum. Parasitology Research, 110, 2509–2513. DOI: 10.1007/s00436-011-2792-7CrossRefGoogle Scholar
  9. Freitas E.O., Nico D., Guan R., Meyer-Fernandes J.R., Clinch K., Evans G.B., et al. 2015. Immucillins Impair Leishmania (L.) infantum chagasi and Leishmania (L.) amazonensis multiplication in vitro. PLoS One, 10, e0124183. DOI: 10.1371/journal.pone.0124183CrossRefGoogle Scholar
  10. Lawton P., Hejl C., Mancassola R., Naciri M., Petavy A.F. 2003. Effects of purine nucleosides on the in vitro growth of Cryptosporidium parvum. FEMS Microbiology Letters, 226, 39–43. DOI: 10.1016/S0378-1097(03)00555-XCrossRefGoogle Scholar
  11. Leroux A.E., Krauth-Siegel R.L. 2015. Thiol redox biology of Trypanosomatids and potential targets for chemotherapy. Molecular and Biochemical Parasitology, DOI: 10.1016/j.molbiopara.2015.11.003Google Scholar
  12. Martin J.L., Yates P.A., Soysa R., Alfaro J.F., Yang F., Burnum-Johnson K.E., et al. 2014. Metabolic reprogramming during purine stress in the protozoan pathogen Leishmania donovani. PLoS Pathogens, 10, e1003938. DOI: 10.1371/journal.ppat.1003938CrossRefGoogle Scholar
  13. Mondal S., Roy J.J., Bera T. 2014. Generation of adenosine tri-phosphate in Leishmania donovani amastigote forms. Acta Parasitologica, 59, 11–16. DOI: 10.2478/s11686-014-0203-9CrossRefGoogle Scholar
  14. Monge-Maillo B., López-Vélez R. 2013. Therapeutic options for visceral leishmaniasis. Drugs, 73, 1863–1888. DOI: 10.1007/s40265-013-0133-0CrossRefGoogle Scholar
  15. Pachioni J. de A., Magalhães J.G., Lima E.J.C., Bueno L. de M., Barbosa J.F., de Sá M.M., Rangel-Yagui C.O., 2013. Alkylphospholipids - a promising class of chemotherapeutic agents with a broad pharmacological spectrum. Journal of Pharmacy and Pharmaceutical Sciences, 16, 742–759. DOI: 10.18433/J3990VCrossRefGoogle Scholar
  16. Serafim T.D., Figueiredo A.B., Costa P.A.C., Marques-da-Silva E.A., Gonçalves R., de Moura S.A.L., et al. 2012. Leishmania metacyclogenesis is promoted in the absence of purines. PLoS Neglected Tropical Diseases, 6, e1833. DOI: 10.1371/journal.pntd.0001833CrossRefGoogle Scholar
  17. Solano-Gallego L., Miró G., Koutinas A., Cardoso L., Pennisi M.G., Ferrer L., et al. 2011. LeishVet guidelines for the practical management of canine leishmaniosis. Parasites & Vectors, 4, 86–102. DOI: 10.1186/1756-3305-4-86CrossRefGoogle Scholar
  18. Soysa R., Wilson Z.N., Elferich J., Forquer I., Shinde U., Riscoe M.K., et al. 2013. Substrate inhibition of uracil phosphoribosyltransferase by uracil can account for the uracil growth sensitivity of Leishmania donovani pyrimidine auxotrophs. Journal of Biological Chemistry, 288, 29954–29964. DOI: 10.1074/jbc.M113.478826CrossRefGoogle Scholar
  19. Sundar S., Chakravarty J. 2013. Leishmaniasis: an update of current pharmacotherapy. Expert Opinion on Pharmacotherapy, 14, 53–63. DOI: 10.1517/14656566.2013.755515CrossRefGoogle Scholar
  20. Vincent I.M., Barrett M.P. 2015. Metabolomic-based strategies for anti-parasite drug discovery. Journal of Biomolecular Screening, 20, 44–55. DOI: 10.1177/1087057114551519CrossRefGoogle Scholar

Copyright information

© Witold Stefański Institute of Parasitology, Polish Academy of Sciences 2017

Authors and Affiliations

  1. 1.Université de LyonUniversité Claude-Bernard Lyon I, ISPB-Faculté de PharmacieLyonFrance
  2. 2.Institut de recherche pour le développement (IRD)UMR InterTryp IRD/CIRADMontpellierFrance

Personalised recommendations