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Recent Progresses in Amebiasis

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Front. Cell. Infect. Microbiol. | doi: 10.3389/fcimb.2019.00180

Bioactivity of Farnesyltransferase Inhibitors against Entamoeba histolytica and Schistosoma mansoni

 Alexandra Probst1, Thi N. Nguyen1, Nelly El-Sakkary1, Danielle Skinner1, Brian M. Suzuki1, Frederick S. Buckner2, Michael H. Gelb2,  Conor R. Caffrey1* and  Anjan Debnath1*
  • 1Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, United States
  • 2University of Washington, United States

The protozoan parasite Entamoeba histolytica can induce amebic colitis and amebic liver abscess. First-line drugs for the treatment of amebiasis are nitroimidazoles, particularly metronidazole. Metronidazole has side effects and potential drug resistance is a concern. Schistosomiasis, a chronic and painful infection, is caused by various species of the Schistosoma flatworm. There is only one partially effective drug, praziquantel, a worrisome situation should drug resistance emerge. As many essential metabolic pathways and enzymes are shared between eukaryotic organisms, it is possible to conceive of small molecule interventions that target more than one organism or target, particularly when chemical matter is already available. Farnesyltransferase (FT), the last common enzyme for products derived from the mevalonate pathway, is vital for diverse functions, including cell differentiation and growth. Both E. histolytica and Schistosoma mansoni genomes encode FT genes. In this study, we phenotypically screened E. histolytica and S. mansoni in vitro with the established FT inhibitors, lonafarnib and tipifarnib, and with 125 tipifarnib analogues previously screened against both the whole organism and/or the FT of Trypanosoma brucei and Trypanosoma cruzi. For E. histolytica, we also explored whether synergy arises by combining lonafarnib and metronidazole or lonafarnib with statins that modulate protein prenylation. We demonstrate the antiamebic and antischistosomal activities of lonafarnib and tipifarnib, and identify 17 tipifarnib analogues with more than 75% growth inhibition at 50 µM against E. histolytica. Apart from five analogues of tipifarnib exhibiting activity against both E. histolytica and S. mansoni, 10 additional analogues demonstrated antischistosomal activity (severe degenerative changes at 10 µM after 24 h). Analysis of the structure-activity relationship available for the T. brucei FT suggests that FT may not be the relevant target in E. histolytica and S. mansoni. For E. histolytica, combination of metronidazole and lonafarnib resulted in synergism for growth inhibition. Also, of a number of statins tested, simvastatin exhibited moderate antiamebic activity which, when combined with lonafarnib, resulted in slight synergism. Even in the absence of a definitive molecular target, identification of potent antiparasitic tipifarnib analogues encourages further exploration while the synergistic combination of metronidazole and lonafarnib offers a promising treatment strategy for amebiasis.

Keywords: Entamoeba histolytica, Schistosoma mansoni, Farnesyltransferase, Metronidazole, lonafarnib, Tipifarnib, statin, chemotherapy

Received: 08 Jan 2019; Accepted: 09 May 2019.

Edited by:

Tomoyoshi Nozaki, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Japan

Reviewed by:

Elisa Azuara-Liceaga, Universidad Autónoma de la Ciudad de México, Mexico
David Leitsch, Medical University of Vienna, Austria  

Copyright: © 2019 Probst, Nguyen, El-Sakkary, Skinner, Suzuki, Buckner, Gelb, Caffrey and Debnath. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Dr. Conor R. Caffrey, Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, 92093, California, United States, ccaffrey@ucsd.edu
Dr. Anjan Debnath, Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, 92093, California, United States, adebnath@ucsd.edu