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dc.contributor.authorMwenechanya, Roy
dc.contributor.authorKovářová, Julie
dc.contributor.authorDickens, Nicholas J.
dc.contributor.authorMudaliar, Manikhandan
dc.contributor.authorHerzyk, Pawel
dc.contributor.authorVincent, Isabel M.
dc.contributor.authorWeidt, Stefan K.
dc.contributor.authorBurgess, Karl E.
dc.contributor.authorBurchmore, Richard J. S.
dc.contributor.authorPountain, Andrew W.
dc.contributor.authorSmith, Terry K.
dc.contributor.authorCreek, Darren J.
dc.contributor.authorKim, Dong-Hyun
dc.contributor.authorLepesheva, Galina I.
dc.contributor.authorBarrett, Michael P.
dc.identifier.citationMwenechanya , R , Kovářová , J , Dickens , N J , Mudaliar , M , Herzyk , P , Vincent , I M , Weidt , S K , Burgess , K E , Burchmore , R J S , Pountain , A W , Smith , T K , Creek , D J , Kim , D-H , Lepesheva , G I & Barrett , M P 2017 , ' Sterol 14α-demethylase mutation leads to amphotericin B resistance in Leishmania mexicana ' , PLoS Neglected Tropical Diseases , vol. 11 , no. 6 , e0005649 .
dc.identifier.otherPURE: 250451098
dc.identifier.otherPURE UUID: 1db64505-5d10-474f-b3ef-a164aa1cbb0c
dc.identifier.otherRIS: urn:E048DF21064FC3005543BFAC9B93C2A6
dc.identifier.otherWOS: 000405080700034
dc.identifier.otherScopus: 85021671814
dc.descriptionThe Wellcome Trust ( funded MB through awards 104111/Z/14/Z and 105614/Z/14/Z. The European Commission ( funded TKS through award number 602773 and JK through award number 290080. The National Institutes of Health ( funded GIL though award number GM067871. The Commonwealth Scholarship Commission ( funded RM through scholarship RM1.en
dc.description.abstractAmphotericin B has emerged as the therapy of choice for use against the leishmaniases. Administration of the drug in its liposomal formulation as a single injection is being promoted in a campaign to bring the leishmaniases under control. Understanding the risks and mechanisms of resistance is therefore of great importance. Here we select amphotericin B-resistant Leishmania mexicana parasites with relative ease. Metabolomic analysis demonstrated that ergosterol, the sterol known to bind the drug, is prevalent in wild-type cells, but diminished in the resistant line, where alternative sterols become prevalent. This indicates that the resistance phenotype is related to loss of drug binding. Comparing sequences of the parasites’ genomes revealed a plethora of single nucleotide polymorphisms that distinguish wild-type and resistant cells, but only one of these was found to be homozygous and associated with a gene encoding an enzyme in the sterol biosynthetic pathway, sterol 14α-demethylase (CYP51). The mutation, N176I, is found outside of the enzyme’s active site, consistent with the fact that the resistant line continues to produce the enzyme’s product. Expression of wild-type sterol 14α-demethylase in the resistant cells caused reversion to drug sensitivity and a restoration of ergosterol synthesis, showing that the mutation is indeed responsible for resistance. The amphotericin B resistant parasites become hypersensitive to pentamidine and also agents that induce oxidative stress. This work reveals the power of combining polyomics approaches, to discover the mechanism underlying drug resistance as well as offering novel insights into the selection of resistance to amphotericin B itself.
dc.relation.ispartofPLoS Neglected Tropical Diseasesen
dc.rights© 2017 Mwenechanya et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en
dc.subjectVisceral leishmaniasisen
dc.subjectDonovani promastigotesen
dc.subjectClinical isolateen
dc.subjectQH301 Biologyen
dc.subjectQD Chemistryen
dc.subjectRM Therapeutics. Pharmacologyen
dc.titleSterol 14α-demethylase mutation leads to amphotericin B resistance in Leishmania mexicanaen
dc.typeJournal articleen
dc.description.versionPublisher PDFen
dc.contributor.institutionUniversity of St Andrews.School of Biologyen
dc.contributor.institutionUniversity of St Andrews.Biomedical Sciences Research Complexen
dc.description.statusPeer revieweden

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