Targeting Ergosterol biosynthesis in Leishmania donovani: essentiality of sterol 14 alpha-demethylase.
Leishmania protozoan parasites (Trypanosomatidae family) are the causative agents of cutaneous, mucocutaneous and visceral leishmaniasis worldwide. While these diseases are associated with significant morbidity and mortality, there are few adequate treatments available. Sterol 14alpha-demethylase (C...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2015-03-01
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| Series: | PLoS Neglected Tropical Diseases |
| Online Access: | http://europepmc.org/articles/PMC4359151?pdf=render |
| _version_ | 1819208927129108480 |
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| author | Laura-Isobel McCall Amale El Aroussi Jun Yong Choi Debora F Vieira Geraldine De Muylder Jonathan B Johnston Steven Chen Danielle Kellar Jair L Siqueira-Neto William R Roush Larissa M Podust James H McKerrow |
| author_facet | Laura-Isobel McCall Amale El Aroussi Jun Yong Choi Debora F Vieira Geraldine De Muylder Jonathan B Johnston Steven Chen Danielle Kellar Jair L Siqueira-Neto William R Roush Larissa M Podust James H McKerrow |
| author_sort | Laura-Isobel McCall |
| collection | DOAJ |
| description | Leishmania protozoan parasites (Trypanosomatidae family) are the causative agents of cutaneous, mucocutaneous and visceral leishmaniasis worldwide. While these diseases are associated with significant morbidity and mortality, there are few adequate treatments available. Sterol 14alpha-demethylase (CYP51) in the parasite sterol biosynthesis pathway has been the focus of considerable interest as a novel drug target in Leishmania. However, its essentiality in Leishmania donovani has yet to be determined. Here, we use a dual biological and pharmacological approach to demonstrate that CYP51 is indispensable in L. donovani. We show via a facilitated knockout approach that chromosomal CYP51 genes can only be knocked out in the presence of episomal complementation and that this episome cannot be lost from the parasite even under negative selection. In addition, we treated wild-type L. donovani and CYP51-deficient strains with 4-aminopyridyl-based inhibitors designed specifically for Trypanosoma cruzi CYP51. While potency was lower than in T. cruzi, these inhibitors had increased efficacy in parasites lacking a CYP51 allele compared to complemented parasites, indicating inhibition of parasite growth via a CYP51-specific mechanism and confirming essentiality of CYP51 in L. donovani. Overall, these results provide support for further development of CYP51 inhibitors for the treatment of visceral leishmaniasis. |
| first_indexed | 2024-12-23T05:47:09Z |
| format | Article |
| id | doaj.art-58924484fcc34757ab91165c0f1e5fe2 |
| institution | Directory Open Access Journal |
| issn | 1935-2727 1935-2735 |
| language | English |
| last_indexed | 2024-12-23T05:47:09Z |
| publishDate | 2015-03-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Neglected Tropical Diseases |
| spelling | doaj.art-58924484fcc34757ab91165c0f1e5fe22022-12-21T17:58:04ZengPublic Library of Science (PLoS)PLoS Neglected Tropical Diseases1935-27271935-27352015-03-0193e000358810.1371/journal.pntd.0003588Targeting Ergosterol biosynthesis in Leishmania donovani: essentiality of sterol 14 alpha-demethylase.Laura-Isobel McCallAmale El AroussiJun Yong ChoiDebora F VieiraGeraldine De MuylderJonathan B JohnstonSteven ChenDanielle KellarJair L Siqueira-NetoWilliam R RoushLarissa M PodustJames H McKerrowLeishmania protozoan parasites (Trypanosomatidae family) are the causative agents of cutaneous, mucocutaneous and visceral leishmaniasis worldwide. While these diseases are associated with significant morbidity and mortality, there are few adequate treatments available. Sterol 14alpha-demethylase (CYP51) in the parasite sterol biosynthesis pathway has been the focus of considerable interest as a novel drug target in Leishmania. However, its essentiality in Leishmania donovani has yet to be determined. Here, we use a dual biological and pharmacological approach to demonstrate that CYP51 is indispensable in L. donovani. We show via a facilitated knockout approach that chromosomal CYP51 genes can only be knocked out in the presence of episomal complementation and that this episome cannot be lost from the parasite even under negative selection. In addition, we treated wild-type L. donovani and CYP51-deficient strains with 4-aminopyridyl-based inhibitors designed specifically for Trypanosoma cruzi CYP51. While potency was lower than in T. cruzi, these inhibitors had increased efficacy in parasites lacking a CYP51 allele compared to complemented parasites, indicating inhibition of parasite growth via a CYP51-specific mechanism and confirming essentiality of CYP51 in L. donovani. Overall, these results provide support for further development of CYP51 inhibitors for the treatment of visceral leishmaniasis.http://europepmc.org/articles/PMC4359151?pdf=render |
| spellingShingle | Laura-Isobel McCall Amale El Aroussi Jun Yong Choi Debora F Vieira Geraldine De Muylder Jonathan B Johnston Steven Chen Danielle Kellar Jair L Siqueira-Neto William R Roush Larissa M Podust James H McKerrow Targeting Ergosterol biosynthesis in Leishmania donovani: essentiality of sterol 14 alpha-demethylase. PLoS Neglected Tropical Diseases |
| title | Targeting Ergosterol biosynthesis in Leishmania donovani: essentiality of sterol 14 alpha-demethylase. |
| title_full | Targeting Ergosterol biosynthesis in Leishmania donovani: essentiality of sterol 14 alpha-demethylase. |
| title_fullStr | Targeting Ergosterol biosynthesis in Leishmania donovani: essentiality of sterol 14 alpha-demethylase. |
| title_full_unstemmed | Targeting Ergosterol biosynthesis in Leishmania donovani: essentiality of sterol 14 alpha-demethylase. |
| title_short | Targeting Ergosterol biosynthesis in Leishmania donovani: essentiality of sterol 14 alpha-demethylase. |
| title_sort | targeting ergosterol biosynthesis in leishmania donovani essentiality of sterol 14 alpha demethylase |
| url | http://europepmc.org/articles/PMC4359151?pdf=render |
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