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...
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ftdoajarticles:oai:doaj.org/article:58924484fcc34757ab91165c0f1e5fe2 2023-05-15T15:07:46+02:00 Targeting Ergosterol biosynthesis in Leishmania donovani: essentiality of sterol 14 alpha-demethylase. 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 2015-03-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0003588 https://doaj.org/article/58924484fcc34757ab91165c0f1e5fe2 EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC4359151?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0003588 https://doaj.org/article/58924484fcc34757ab91165c0f1e5fe2 PLoS Neglected Tropical Diseases, Vol 9, Iss 3, p e0003588 (2015) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2015 ftdoajarticles https://doi.org/10.1371/journal.pntd.0003588 2022-12-31T14:05:25Z 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. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 9 3 e0003588 |
institution |
Open Polar |
collection |
Directory of Open Access Journals: DOAJ Articles |
op_collection_id |
ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
spellingShingle |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 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. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
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. |
format |
Article in Journal/Newspaper |
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 |
title |
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_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_sort |
targeting ergosterol biosynthesis in leishmania donovani: essentiality of sterol 14 alpha-demethylase. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2015 |
url |
https://doi.org/10.1371/journal.pntd.0003588 https://doaj.org/article/58924484fcc34757ab91165c0f1e5fe2 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 9, Iss 3, p e0003588 (2015) |
op_relation |
http://europepmc.org/articles/PMC4359151?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0003588 https://doaj.org/article/58924484fcc34757ab91165c0f1e5fe2 |
op_doi |
https://doi.org/10.1371/journal.pntd.0003588 |
container_title |
PLOS Neglected Tropical Diseases |
container_volume |
9 |
container_issue |
3 |
container_start_page |
e0003588 |
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1766339193758285824 |