CYP51 is an essential drug target for the treatment of primary amoebic meningoencephalitis (PAM).
Primary Amoebic Meningoencephalitis (PAM) is caused by Naegleria fowleri, a free-living amoeba that occasionally infects humans. While considered "rare" (but likely underreported) the high mortality rate and lack of established success in treatment makes PAM a particularly devastating infe...
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ftdoajarticles:oai:doaj.org/article:553d08f0e7b9437eabf9c8b31e039082 2023-05-15T15:12:46+02:00 CYP51 is an essential drug target for the treatment of primary amoebic meningoencephalitis (PAM). Anjan Debnath Claudia M Calvet Gareth Jennings Wenxu Zhou Alexander Aksenov Madeline R Luth Ruben Abagyan W David Nes James H McKerrow Larissa M Podust 2017-12-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0006104 https://doaj.org/article/553d08f0e7b9437eabf9c8b31e039082 EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC5746216?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0006104 https://doaj.org/article/553d08f0e7b9437eabf9c8b31e039082 PLoS Neglected Tropical Diseases, Vol 11, Iss 12, p e0006104 (2017) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2017 ftdoajarticles https://doi.org/10.1371/journal.pntd.0006104 2022-12-31T09:24:34Z Primary Amoebic Meningoencephalitis (PAM) is caused by Naegleria fowleri, a free-living amoeba that occasionally infects humans. While considered "rare" (but likely underreported) the high mortality rate and lack of established success in treatment makes PAM a particularly devastating infection. In the absence of economic inducements to invest in development of anti-PAM drugs by the pharmaceutical industry, anti-PAM drug discovery largely relies on drug 'repurposing'-a cost effective strategy to apply known drugs for treatment of rare or neglected diseases. Similar to fungi, N. fowleri has an essential requirement for ergosterol, a building block of plasma and cell membranes. Disruption of sterol biosynthesis by small-molecule inhibitors is a validated interventional strategy against fungal pathogens of medical and agricultural importance. The N. fowleri genome encodes the sterol 14-demethylase (CYP51) target sharing ~35% sequence identity to fungal orthologues. The similarity of targets raises the possibility of repurposing anti-mycotic drugs and optimization of their usage for the treatment of PAM. In this work, we (i) systematically assessed the impact of anti-fungal azole drugs, known as conazoles, on sterol biosynthesis and viability of cultured N. fowleri trophozotes, (ii) identified the endogenous CYP51 substrate by mass spectrometry analysis of N. fowleri lipids, and (iii) analyzed the interactions between the recombinant CYP51 target and conazoles by UV-vis spectroscopy and x-ray crystallography. Collectively, the target-based and parasite-based data obtained in these studies validated CYP51 as a potentially 'druggable' target in N. fowleri, and conazole drugs as the candidates for assessment in the animal model of PAM. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 11 12 e0006104 |
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Open Polar |
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Directory of Open Access Journals: DOAJ Articles |
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ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Anjan Debnath Claudia M Calvet Gareth Jennings Wenxu Zhou Alexander Aksenov Madeline R Luth Ruben Abagyan W David Nes James H McKerrow Larissa M Podust CYP51 is an essential drug target for the treatment of primary amoebic meningoencephalitis (PAM). |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
Primary Amoebic Meningoencephalitis (PAM) is caused by Naegleria fowleri, a free-living amoeba that occasionally infects humans. While considered "rare" (but likely underreported) the high mortality rate and lack of established success in treatment makes PAM a particularly devastating infection. In the absence of economic inducements to invest in development of anti-PAM drugs by the pharmaceutical industry, anti-PAM drug discovery largely relies on drug 'repurposing'-a cost effective strategy to apply known drugs for treatment of rare or neglected diseases. Similar to fungi, N. fowleri has an essential requirement for ergosterol, a building block of plasma and cell membranes. Disruption of sterol biosynthesis by small-molecule inhibitors is a validated interventional strategy against fungal pathogens of medical and agricultural importance. The N. fowleri genome encodes the sterol 14-demethylase (CYP51) target sharing ~35% sequence identity to fungal orthologues. The similarity of targets raises the possibility of repurposing anti-mycotic drugs and optimization of their usage for the treatment of PAM. In this work, we (i) systematically assessed the impact of anti-fungal azole drugs, known as conazoles, on sterol biosynthesis and viability of cultured N. fowleri trophozotes, (ii) identified the endogenous CYP51 substrate by mass spectrometry analysis of N. fowleri lipids, and (iii) analyzed the interactions between the recombinant CYP51 target and conazoles by UV-vis spectroscopy and x-ray crystallography. Collectively, the target-based and parasite-based data obtained in these studies validated CYP51 as a potentially 'druggable' target in N. fowleri, and conazole drugs as the candidates for assessment in the animal model of PAM. |
format |
Article in Journal/Newspaper |
author |
Anjan Debnath Claudia M Calvet Gareth Jennings Wenxu Zhou Alexander Aksenov Madeline R Luth Ruben Abagyan W David Nes James H McKerrow Larissa M Podust |
author_facet |
Anjan Debnath Claudia M Calvet Gareth Jennings Wenxu Zhou Alexander Aksenov Madeline R Luth Ruben Abagyan W David Nes James H McKerrow Larissa M Podust |
author_sort |
Anjan Debnath |
title |
CYP51 is an essential drug target for the treatment of primary amoebic meningoencephalitis (PAM). |
title_short |
CYP51 is an essential drug target for the treatment of primary amoebic meningoencephalitis (PAM). |
title_full |
CYP51 is an essential drug target for the treatment of primary amoebic meningoencephalitis (PAM). |
title_fullStr |
CYP51 is an essential drug target for the treatment of primary amoebic meningoencephalitis (PAM). |
title_full_unstemmed |
CYP51 is an essential drug target for the treatment of primary amoebic meningoencephalitis (PAM). |
title_sort |
cyp51 is an essential drug target for the treatment of primary amoebic meningoencephalitis (pam). |
publisher |
Public Library of Science (PLoS) |
publishDate |
2017 |
url |
https://doi.org/10.1371/journal.pntd.0006104 https://doaj.org/article/553d08f0e7b9437eabf9c8b31e039082 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 11, Iss 12, p e0006104 (2017) |
op_relation |
http://europepmc.org/articles/PMC5746216?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0006104 https://doaj.org/article/553d08f0e7b9437eabf9c8b31e039082 |
op_doi |
https://doi.org/10.1371/journal.pntd.0006104 |
container_title |
PLOS Neglected Tropical Diseases |
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11 |
container_issue |
12 |
container_start_page |
e0006104 |
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1766343402637492224 |