{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T19:52:07Z","timestamp":1792525927900,"version":"4.5.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1012382","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,7,23]],"date-time":"2024-07-23T00:00:00Z","timestamp":1721692800000}}],"reference-count":65,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2024,7,11]],"date-time":"2024-07-11T00:00:00Z","timestamp":1720656000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["203134\/Z\/16\/Z"],"award-info":[{"award-number":["203134\/Z\/16\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["218448\/Z\/19\/Z"],"award-info":[{"award-number":["218448\/Z\/19\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/S019650\/1"],"award-info":[{"award-number":["MR\/S019650\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Liposomal amphotericin B is an important frontline drug for the treatment of visceral leishmaniasis, a neglected disease of poverty. The mechanism of action of amphotericin B (AmB) is thought to involve interaction with ergosterol and other ergostane sterols, resulting in disruption of the integrity and key functions of the plasma membrane. Emergence of clinically refractory isolates of <jats:italic>Leishmania donovani<\/jats:italic> and <jats:italic>L<\/jats:italic>. <jats:italic>infantum<\/jats:italic> is an ongoing issue and knowledge of potential resistance mechanisms can help to alleviate this problem. Here we report the characterisation of four independently selected <jats:italic>L<\/jats:italic>. <jats:italic>donovani<\/jats:italic> clones that are resistant to AmB. Whole genome sequencing revealed that in three of the moderately resistant clones, resistance was due solely to the deletion of a gene encoding C24-sterol methyltransferase (<jats:italic>SMT1<\/jats:italic>). The fourth, hyper-resistant resistant clone (&gt;60-fold) was found to have a 24 bp deletion in both alleles of a gene encoding a putative cytochrome P450 reductase (P450R1). Metabolic profiling indicated these parasites were virtually devoid of ergosterol (0.2% versus 18% of total sterols in wild-type) and had a marked accumulation of 14-methylfecosterol (75% versus 0.1% of total sterols in wild-type) and other 14-alpha methylcholestanes. These are substrates for sterol 14-alpha demethylase (<jats:italic>CYP51<\/jats:italic>) suggesting that this enzyme may be a <jats:italic>bona fide<\/jats:italic> P450R specifically involved in electron transfer from NADPH to CYP51 during catalysis. Deletion of <jats:italic>P450R1<\/jats:italic> in wild-type cells phenocopied the metabolic changes observed in our AmB hyper-resistant clone as well as in CYP51 nulls. Likewise, addition of a wild type <jats:italic>P450R1<\/jats:italic> gene restored sterol profiles to wild type. Our studies indicate that P450R1 is essential for <jats:italic>L<\/jats:italic>. <jats:italic>donovani<\/jats:italic> amastigote viability, thus loss of this gene is unlikely to be a driver of clinical resistance. Nevertheless, investigating the mechanisms underpinning AmB resistance in these cells provided insights that refine our understanding of the <jats:italic>L<\/jats:italic>. <jats:italic>donovani<\/jats:italic> sterol biosynthetic pathway.<\/jats:p>","DOI":"10.1371\/journal.ppat.1012382","type":"journal-article","created":{"date-parts":[[2024,7,11]],"date-time":"2024-07-11T18:02:23Z","timestamp":1720720943000},"page":"e1012382","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":20,"title":["Sterol 14-alpha demethylase (CYP51) activity in Leishmania donovani is likely dependent upon cytochrome P450 reductase 1"],"prefix":"10.1371","volume":"20","author":[{"given":"Lindsay B.","family":"Tulloch","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Tinti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard J.","family":"Wall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan K.","family":"Weidt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoriano","family":"Corpas- Lopez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gourav","family":"Dey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terry K.","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan H.","family":"Fairlamb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael P.","family":"Barrett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8810-5605","authenticated-orcid":true,"given":"Susan","family":"Wyllie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,7,11]]},"reference":[{"key":"ppat.1012382.ref001","author":"WHO","year":"2023","journal-title":"Leishmaniasis"},{"issue":"2","key":"ppat.1012382.ref002","doi-asserted-by":"crossref","first-page":"151","DOI":"10.4103\/0974-777X.62883","article-title":"Treatment of visceral leishmaniasis.","volume":"2","author":"EM Moore","year":"2010","journal-title":"J Glob Infect Dis"},{"issue":"2","key":"ppat.1012382.ref003","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1007\/s40121-022-00602-2","article-title":"Treatment of Cutaneous Leishmaniasis and Insights into Species-Specific Responses: A Narrative Review.","volume":"11","author":"RK Madusanka","year":"2022","journal-title":"Infect Dis Ther."},{"issue":"4","key":"ppat.1012382.ref004","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1093\/jac\/dkx516","article-title":"What to expect and when: benznidazole toxicity in chronic Chagas\u2019 disease treatment","volume":"73","author":"E Aldasoro","year":"2018","journal-title":"The Journal of antimicrobial chemotherapy"},{"issue":"2","key":"ppat.1012382.ref005","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1586\/14787210.4.2.177","article-title":"Miltefosine: oral treatment of leishmaniasis.","volume":"4","author":"J Soto","year":"2006","journal-title":"Expert review of anti-infective therapy."},{"issue":"1","key":"ppat.1012382.ref006","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1128\/CMR.19.1.111-126.2006","article-title":"Drug resistance in leishmaniasis","volume":"19","author":"SL Croft","year":"2006","journal-title":"Clinical microbiology reviews"},{"issue":"11","key":"ppat.1012382.ref007","doi-asserted-by":"crossref","first-page":"1530","DOI":"10.1093\/cid\/cit102","article-title":"Increasing failure of miltefosine in the treatment of Kala-azar in Nepal and the potential role of parasite drug resistance, reinfection, or noncompliance","volume":"56","author":"S Rijal","year":"2013","journal-title":"Clin Infect Dis"},{"issue":"5","key":"ppat.1012382.ref008","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1080\/00034983.1998.11813313","article-title":"Do the diminishing efficacy and increasing toxicity of sodium stibogluconate in the treatment of visceral leishmaniasis in Bihar, India, justify its continued use as a first-line drug? 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