{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T00:05:39Z","timestamp":1781309139251,"version":"3.54.1"},"reference-count":81,"publisher":"eLife Sciences Publications, Ltd","license":[{"start":{"date-parts":[[2020,8,11]],"date-time":"2020-08-11T00:00:00Z","timestamp":1597104000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2020,8,11]],"date-time":"2020-08-11T00:00:00Z","timestamp":1597104000000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2020,8,11]],"date-time":"2020-08-11T00:00:00Z","timestamp":1597104000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["G0701258"],"award-info":[{"award-number":["G0701258"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["GM111749"],"award-info":[{"award-number":["GM111749"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/R015791\/1"],"award-info":[{"award-number":["MR\/R015791\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000708","name":"Scottish Universities Physics Alliance","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000708","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100016249","name":"Albaha University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100016249","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Science Without Borders, Brazil","award":["206385\/2014-5"],"award-info":[{"award-number":["206385\/2014-5"]}]},{"DOI":"10.13039\/100004440","name":"Wellcome","doi-asserted-by":"publisher","award":["204697\/Z\/16\/Z"],"award-info":[{"award-number":["204697\/Z\/16\/Z"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Cambridge trust"},{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000288","name":"Royal Society","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000288","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elifesciences.org"],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>\n                    Mutations in the\n                    <jats:italic>Trypanosoma brucei<\/jats:italic>\n                    aquaporin AQP2 are associated with resistance to pentamidine and melarsoprol. We show that TbAQP2 but not TbAQP3 was positively selected for increased pore size from a common ancestor aquaporin. We demonstrate that TbAQP2\u2019s unique architecture permits pentamidine permeation through its central pore and show how specific mutations in highly conserved motifs affect drug permeation. Introduction of key TbAQP2 amino acids into TbAQP3 renders the latter permeable to pentamidine. Molecular dynamics demonstrates that permeation by dicationic pentamidine is energetically favourable in TbAQP2, driven by the membrane potential, although aquaporins are normally strictly impermeable for ionic species. We also identify the structural determinants that make pentamidine a permeant although most other diamidine drugs are excluded. Our results have wide-ranging implications for optimising antitrypanosomal drugs and averting cross-resistance. Moreover, these new insights in aquaporin permeation may allow the pharmacological exploitation of other members of this ubiquitous gene family.\n                  <\/jats:p>","DOI":"10.7554\/elife.56416","type":"journal-article","created":{"date-parts":[[2020,8,7]],"date-time":"2020-08-07T08:01:30Z","timestamp":1596787290000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.56416","source":"Crossref","is-referenced-by-count":39,"title":["Positively selected modifications in the pore of TbAQP2 allow pentamidine to enter Trypanosoma brucei"],"prefix":"10.7554","volume":"9","author":[{"given":"Ali H","family":"Alghamdi","sequence":"first","affiliation":[{"name":"Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane C","family":"Munday","sequence":"additional","affiliation":[{"name":"Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6542-0485","authenticated-orcid":true,"given":"Gustavo Daniel","family":"Campagnaro","sequence":"additional","affiliation":[{"name":"Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominik","family":"Gurvic","sequence":"additional","affiliation":[{"name":"Computational Biology Centre for Translational and Interdisciplinary Research, University of Dundee, Dundee, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fredrik","family":"Svensson","sequence":"additional","affiliation":[{"name":"IOTA Pharmaceuticals Ltd, St Johns Innovation Centre, Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chinyere E","family":"Okpara","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Liverpool, Liverpool, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arvind","family":"Kumar","sequence":"additional","affiliation":[{"name":"Chemistry Department, Georgia State University, Atlanta, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Quintana","sequence":"additional","affiliation":[{"name":"School of Life Sciences, University of Dundee, Dundee, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Esther","family":"Martin Abril","sequence":"additional","affiliation":[{"name":"Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrik","family":"Mili\u0107","sequence":"additional","affiliation":[{"name":"Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Watson","sequence":"additional","affiliation":[{"name":"Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Paape","sequence":"additional","affiliation":[{"name":"Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Settimo","sequence":"additional","affiliation":[{"name":"Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Dimitriou","sequence":"additional","affiliation":[{"name":"Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna","family":"Wielinska","sequence":"additional","affiliation":[{"name":"Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graeme","family":"Smart","sequence":"additional","affiliation":[{"name":"Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura F","family":"Anderson","sequence":"additional","affiliation":[{"name":"Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher M","family":"Woodley","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Liverpool, Liverpool, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siu Pui Ying","family":"Kelly","sequence":"additional","affiliation":[{"name":"Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hasan MS","family":"Ibrahim","sequence":"additional","affiliation":[{"name":"Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7470-3484","authenticated-orcid":true,"given":"Fabian","family":"Hulpia","sequence":"additional","affiliation":[{"name":"Laboratory for Medicinal Chemistry, University of Ghent, Ghent, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed I","family":"Al-Salabi","sequence":"additional","affiliation":[{"name":"Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4821-1689","authenticated-orcid":true,"given":"Anthonius A","family":"Eze","sequence":"additional","affiliation":[{"name":"Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Sprenger","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ibrahim A","family":"Teka","sequence":"additional","affiliation":[{"name":"Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Gudin","sequence":"additional","affiliation":[{"name":"Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Weyand","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Field","sequence":"additional","affiliation":[{"name":"School of Life Sciences, University of Dundee, Dundee, United Kingdom"},{"name":"Institute of Parasitology, Biology Centre, Czech Academy of Sciences, Ceske Budejovice, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Dardonville","sequence":"additional","affiliation":[{"name":"Instituto de Qu\u00edmica M\u00e9dica - CSIC, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard R","family":"Tidwell","sequence":"additional","affiliation":[{"name":"Department of Pathology and Lab Medicine, University of North Carolina at Chapel Hill, Chapel Hill, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6435-7266","authenticated-orcid":true,"given":"Mark","family":"Carrington","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"O'Neill","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Liverpool, Liverpool, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David W","family":"Boykin","sequence":"additional","affiliation":[{"name":"Chemistry Department, Georgia State University, Atlanta, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrich","family":"Zachariae","sequence":"additional","affiliation":[{"name":"Computational Biology Centre for Translational and Interdisciplinary Research, University of Dundee, Dundee, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9963-1827","authenticated-orcid":true,"given":"Harry P","family":"De Koning","sequence":"additional","affiliation":[{"name":"Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2020,8,11]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"GROMACS: high performance molecular simulations through multi-level parallelism from laptops to supercomputers","volume":"1-2","author":"Abraham","year":"2015","journal-title":"SoftwareX"},{"key":"bib2","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1124\/mol.114.096016","article-title":"Potent trypanocidal curcumin analogs bearing a monoenone linker motif act on Trypanosoma brucei by forming an adduct with trypanothione","volume":"87","author":"Alkhaldi","year":"2015","journal-title":"Molecular Pharmacology"},{"key":"bib3","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.ijpddr.2015.12.002","article-title":"Trypanocidal action of bisphosphonium salts through a mitochondrial target in bloodstream form Trypanosoma brucei","volume":"6","author":"Alkhaldi","year":"2016","journal-title":"International Journal for Parasitology: Drugs and Drug Resistance"},{"key":"bib4","doi-asserted-by":"publisher","first-page":"4991","DOI":"10.1093\/emboj\/cdg481","article-title":"Clathrin-mediated endocytosis is essential in Trypanosoma brucei","volume":"22","author":"Allen","year":"2003","journal-title":"The EMBO Journal"},{"key":"bib5","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1016\/j.molbiopara.2005.08.009","article-title":"Tagging a T. brucei RRNA locus improves stable transfection efficiency and circumvents inducible expression position effects","volume":"144","author":"Alsford","year":"2005","journal-title":"Molecular and Biochemical Parasitology"},{"key":"bib6","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1038\/nature10771","article-title":"High-throughput decoding of antitrypanosomal drug efficacy and resistance","volume":"482","author":"Alsford","year":"2012","journal-title":"Nature"},{"key":"bib7","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.molbiopara.2008.05.006","article-title":"Single-locus targeting constructs for reliable regulated RNAi and transgene expression in Trypanosoma brucei","volume":"161","author":"Alsford","year":"2008","journal-title":"Molecular and Biochemical Parasitology"},{"key":"bib8","doi-asserted-by":"publisher","first-page":"10996","DOI":"10.1073\/pnas.1202885109","article-title":"Aquaglyceroporin 2 controls susceptibility to melarsoprol and pentamidine in African trypanosomes","volume":"109","author":"Baker","year":"2012","journal-title":"PNAS"},{"key":"bib9","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1016\/j.pt.2012.12.005","article-title":"Drug resistance in african trypanosomiasis: the melarsoprol and pentamidine story","volume":"29","author":"Baker","year":"2013","journal-title":"Trends in Parasitology"},{"key":"bib10","doi-asserted-by":"publisher","first-page":"1037","DOI":"10.2217\/fmb.11.88","article-title":"Drug resistance in human african trypanosomiasis","volume":"6","author":"Barrett","year":"2011","journal-title":"Future Microbiology"},{"key":"bib11","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1073\/pnas.0507225103","article-title":"Point mutations in the aromatic\/arginine region in aquaporin 1 allow passage of urea, glycerol, Ammonia, and protons","volume":"103","author":"Beitz","year":"2006","journal-title":"PNAS"},{"key":"bib12","doi-asserted-by":"publisher","first-page":"4383","DOI":"10.1021\/jm501853m","article-title":"A survey of the role of noncovalent sulfur interactions in drug design","volume":"58","author":"Beno","year":"2015","journal-title":"Journal of Medicinal Chemistry"},{"key":"bib13","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1021\/ci7002494","article-title":"Small molecule conformational preferences derived from crystal structure data. A medicinal chemistry focused analysis","volume":"48","author":"Brameld","year":"2008","journal-title":"Journal of Chemical Information and Modeling"},{"key":"bib14","doi-asserted-by":"publisher","first-page":"1098","DOI":"10.1124\/mol.106.031351","article-title":"Loss of the high-affinity pentamidine transporter is responsible for high levels of cross-resistance between arsenical and diamidine drugs in african trypanosomes","volume":"71","author":"Bridges","year":"2007","journal-title":"Molecular Pharmacology"},{"key":"bib15","doi-asserted-by":"publisher","first-page":"2397","DOI":"10.1016\/S0140-6736(17)31510-6","article-title":"Human african trypanosomiasis","volume":"390","author":"B\u00fcscher","year":"2017","journal-title":"The Lancet"},{"key":"bib16","doi-asserted-by":"publisher","first-page":"28153","DOI":"10.1074\/jbc.270.47.28153","article-title":"Uptake of diamidine drugs by the P2 nucleoside transporter in melarsen-sensitive and -resistant Trypanosoma brucei brucei","volume":"270","author":"Carter","year":"1995","journal-title":"The Journal of Biological Chemistry"},{"key":"bib17","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1038\/361173a0","article-title":"Arsenical-resistant trypanosomes lack an unusual adenosine transporter","volume":"361","author":"Carter","year":"1993","journal-title":"Nature"},{"key":"bib18","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1590\/0074-0276140497","article-title":"Megazol and its bioisostere 4H-1,2,4-triazole: comparing the trypanocidal, cytotoxic and genotoxic activities and their in vitro and in silico interactions with the Trypanosoma brucei nitroreductase enzyme","volume":"109","author":"Carvalho","year":"2014","journal-title":"Mem\u00f3rias Do Instituto Oswaldo Cruz"},{"key":"bib19","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1021\/ol9025364","article-title":"Strong conformational preferences of heteroaromatic ethers and electron pair repulsion","volume":"12","author":"Chein","year":"2010","journal-title":"Organic Letters"},{"key":"bib20","doi-asserted-by":"publisher","first-page":"9486","DOI":"10.1074\/jbc.273.16.9486","article-title":"Characterization of a nucleoside\/proton symporter in procyclic Trypanosoma brucei brucei","volume":"273","author":"de Koning","year":"1998","journal-title":"Journal of Biological Chemistry"},{"key":"bib21","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1016\/S0166-6851(99)00206-6","article-title":"Further evidence for a link between melarsoprol resistance and P2 transporter function in african trypanosomes","volume":"106","author":"de Koning","year":"2000","journal-title":"Molecular and Biochemical Parasitology"},{"key":"bib22","doi-asserted-by":"publisher","first-page":"586","DOI":"10.1124\/mol.59.3.586","article-title":"Uptake of pentamidine in Trypanosoma brucei brucei is mediated by three distinct transporters: implications for cross-resistance with arsenicals","volume":"59","author":"de Koning","year":"2001","journal-title":"Molecular Pharmacology"},{"key":"bib23","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1016\/S0020-7519(01)00167-9","article-title":"Transporters in african trypanosomes: role in drug action and resistance","volume":"31","author":"de Koning","year":"2001","journal-title":"International Journal for Parasitology"},{"key":"bib24","doi-asserted-by":"publisher","first-page":"1515","DOI":"10.1128\/AAC.48.5.1515-1519.2004","article-title":"The trypanocide diminazene aceturate is accumulated predominantly through the TbAT1 purine transporter: additional insights on diamidine resistance in african trypanosomes","volume":"48","author":"de Koning","year":"2004","journal-title":"Antimicrobial Agents and Chemotherapy"},{"key":"bib25","doi-asserted-by":"publisher","first-page":"1102","DOI":"10.1111\/j.1432-1033.1997.01102.x","article-title":"Hypoxanthine uptake through a purine-selective nucleobase transporter in Trypanosoma brucei brucei procyclic cells is driven by protonmotive force","volume":"247","author":"de Koning","year":"1997","journal-title":"European Journal of Biochemistry"},{"key":"bib26","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/S0166-6851(97)00129-1","article-title":"Purine nucleobase transport in bloodstream forms of Trypanosoma brucei is mediated by two novel transporters","volume":"89","author":"de Koning","year":"1997","journal-title":"Molecular and Biochemical Parasitology"},{"key":"bib27","doi-asserted-by":"publisher","first-page":"853","DOI":"10.1139\/o98-086","article-title":"A highly selective, high-affinity transporter for uracil in Trypanosoma brucei Brucei: evidence for proton-dependent transport","volume":"76","author":"de Koning","year":"1998","journal-title":"Biochemistry and Cell Biology"},{"key":"bib28","doi-asserted-by":"publisher","first-page":"1162","DOI":"10.1124\/mol.56.6.1162","article-title":"Adenosine transporters in bloodstream forms of Trypanosoma brucei: substrate recognition motifs and affinity for trypanocidal drugs","volume":"56","author":"de Koning","year":"1999","journal-title":"Molecular Pharmacology"},{"key":"bib29","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/S0001-706X(01)00177-2","article-title":"Uptake of pentamidine in Trypanosoma brucei is mediated by the P2 adenosine transporter and at least one novel, unrelated transporter","volume":"80","author":"de Koning","year":"2001","journal-title":"Acta Tropica"},{"key":"bib30","doi-asserted-by":"publisher","first-page":"2351","DOI":"10.1242\/jcs.146894","article-title":"The endocytic activity of the flagellar pocket in Trypanosoma brucei is regulated by an adjacent phosphatidylinositol phosphate kinase","volume":"127","author":"Demmel","year":"2014","journal-title":"Journal of Cell Science"},{"key":"bib31","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1016\/0166-6851(92)90023-D","article-title":"Characterisation of melarsen-resistant Trypanosoma brucei brucei with respect to cross-resistance to other drugs and trypanothione metabolism","volume":"53","author":"Fairlamb","year":"1992","journal-title":"Molecular and Biochemical Parasitology"},{"key":"bib32","doi-asserted-by":"publisher","first-page":"775","DOI":"10.1038\/nrmicro2221","article-title":"The trypanosome flagellar pocket","volume":"7","author":"Field","year":"2009","journal-title":"Nature Reviews Microbiology"},{"key":"bib33","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1016\/0166-6851(87)90142-3","article-title":"Flow cytofluorimetric analysis of drug accumulation by multidrug-resistant Trypanosoma brucei and T. b. rhodesiense","volume":"26","author":"Frommel","year":"1987","journal-title":"Molecular and Biochemical Parasitology"},{"key":"bib34","doi-asserted-by":"publisher","first-page":"747","DOI":"10.1007\/s10534-017-0042-x","article-title":"Role of AQP9 in transport of monomethyselenic acid and selenite","volume":"30","author":"Geng","year":"2017","journal-title":"BioMetals"},{"key":"bib35","doi-asserted-by":"publisher","first-page":"4447","DOI":"10.1128\/MCB.00699-14","article-title":"Substrate-induced ubiquitylation and endocytosis of yeast amino acid permeases","volume":"34","author":"Ghaddar","year":"2014","journal-title":"Molecular and Cellular Biology"},{"key":"bib36","doi-asserted-by":"publisher","first-page":"1862","DOI":"10.1017\/S0031182016001268","article-title":"The animal trypanosomiases and their chemotherapy: a review","volume":"143","author":"Giordani","year":"2016","journal-title":"Parasitology"},{"key":"bib37","doi-asserted-by":"publisher","first-page":"404","DOI":"10.1039\/b719777b","article-title":"The nucleobase-ascorbate transporter (NAT) family: genomics, evolution, structure-function relationships and physiological role","volume":"4","author":"Gournas","year":"2008","journal-title":"Molecular BioSystems"},{"key":"bib38","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1111\/j.1365-2958.2009.06997.x","article-title":"Transport-dependent endocytosis and turnover of a uric acid-xanthine permease","volume":"75","author":"Gournas","year":"2010","journal-title":"Molecular Microbiology"},{"key":"bib39","doi-asserted-by":"publisher","first-page":"2819","DOI":"10.1091\/mbc.e17-02-0104","article-title":"Transition of yeast Can1 transporter to the inward-facing state unveils an \u03b1-arrestin target sequence promoting its ubiquitylation and endocytosis","volume":"28","author":"Gournas","year":"2017","journal-title":"Molecular Biology of the Cell"},{"key":"bib40","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0002475","article-title":"Aquaporin 2 mutations in Trypanosoma brucei gambiense field isolates correlate with decreased susceptibility to pentamidine and melarsoprol","volume":"7","author":"Graf","year":"2013","journal-title":"PLOS Neglected Tropical Diseases"},{"key":"bib41","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/j.ijpddr.2015.04.002","article-title":"Chimerization at the AQP2-AQP3 locus is the genetic basis of melarsoprol-pentamidine cross-resistance in clinical Trypanosoma brucei gambiense isolates","volume":"5","author":"Graf","year":"2015","journal-title":"International Journal for Parasitology: Drugs and Drug Resistance"},{"key":"bib42","doi-asserted-by":"publisher","first-page":"3387","DOI":"10.1007\/s00018-016-2173-6","article-title":"Comparative genomics of drug resistance of the sleeping sickness parasite Trypanosoma brucei rhodesiense","volume":"73","author":"Graf","year":"2016","journal-title":"Cellular and Molecular Life Sciences : CMLS"},{"key":"bib43","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1016\/j.meegid.2015.10.018","article-title":"Rediscovery of Trypanosoma ( Pycnomonas ) suis , a tsetse-transmitted trypanosome closely related to T. brucei","volume":"36","author":"Hutchinson","year":"2015","journal-title":"Infection, Genetics and Evolution"},{"key":"bib44","doi-asserted-by":"publisher","first-page":"2690","DOI":"10.1103\/PhysRevLett.78.2690","article-title":"Nonequilibrium equality for free energy differences","volume":"78","author":"Jarzynski","year":"1997","journal-title":"Physical Review Letters"},{"key":"bib45","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1006307","article-title":"Aquaglyceroporin-null trypanosomes display glycerol transport defects and respiratory-inhibitor sensitivity","volume":"13","author":"Jeacock","year":"2017","journal-title":"PLOS Pathogens"},{"key":"bib46","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2164-15-911","article-title":"Extensive stage-regulation of translation revealed by ribosome profiling of Trypanosoma brucei","volume":"15","author":"Jensen","year":"2014","journal-title":"BMC Genomics"},{"key":"bib47","doi-asserted-by":"publisher","first-page":"1859","DOI":"10.1002\/jcc.20945","article-title":"CHARMM-GUI: a web-based graphical user interface for CHARMM","volume":"29","author":"Jo","year":"2008","journal-title":"Journal of Computational Chemistry"},{"key":"bib48","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1016\/j.mam.2013.01.001","article-title":"The SLC1 high-affinity glutamate and neutral amino acid transporter family","volume":"34","author":"Kanai","year":"2013","journal-title":"Molecular Aspects of Medicine"},{"key":"bib49","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1111\/tra.12039","article-title":"Quality control and substrate-dependent downregulation of the nutrient transporter Fur4","volume":"14","author":"Keener","year":"2013","journal-title":"Traffic"},{"key":"bib50","doi-asserted-by":"publisher","first-page":"7830","DOI":"10.1021\/jp101759q","article-title":"Update of the CHARMM all-atom additive force field for lipids: validation on six lipid types","volume":"114","author":"Klauda","year":"2010","journal-title":"The Journal of Physical Chemistry B"},{"key":"bib51","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1111\/j.1550-7408.1975.tb00943.x","article-title":"Protein uptake and digestion in bloodstream and culture forms of Trypanosoma brucei","volume":"22","author":"Langreth","year":"1975","journal-title":"The Journal of Protozoology"},{"key":"bib52","doi-asserted-by":"publisher","first-page":"555","DOI":"10.2174\/138161207780162809","article-title":"Chemotherapeutic strategies against Trypanosoma brucei: drug targets vs. drug targeting","volume":"13","author":"L\u00fcscher","year":"2007","journal-title":"Current Pharmaceutical Design"},{"key":"bib53","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1126\/science.285.5425.242","article-title":"Nucleoside transporter from Trypanosoma brucei involved in drug resistance","volume":"285","author":"M\u00e4ser","year":"1999","journal-title":"Science"},{"key":"bib54","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0067327","article-title":"Identification and functional characterisation of CRK12:cyc9, a novel Cyclin-Dependent kinase (CDK)-Cyclin complex in Trypanosoma brucei","volume":"8","author":"Monnerat","year":"2013","journal-title":"PLOS ONE"},{"key":"bib55","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1016\/S1471-4922(02)02392-9","article-title":"The endocytic apparatus of the kinetoplastida. part II: machinery and components of the system","volume":"18","author":"Morgan","year":"2002","journal-title":"Trends in Parasitology"},{"key":"bib56","doi-asserted-by":"publisher","first-page":"651","DOI":"10.1093\/jac\/dkt442","article-title":"Trypanosoma brucei aquaglyceroporin 2 is a high-affinity transporter for pentamidine and melaminophenyl arsenic drugs and the main genetic determinant of resistance to these drugs","volume":"69","author":"Munday","year":"2014","journal-title":"Journal of Antimicrobial Chemotherapy"},{"key":"bib57","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2015.00032","article-title":"Transport proteins determine drug sensitivity and resistance in a protozoan parasite, Trypanosoma brucei","volume":"6","author":"Munday","year":"2015","journal-title":"Frontiers in Pharmacology"},{"key":"bib58","doi-asserted-by":"publisher","first-page":"887","DOI":"10.1111\/mmi.12979","article-title":"Functional analysis of drug resistance-associated mutations in the Trypanosoma brucei adenosine transporter 1 (TbAT1) and the proposal of a structural model for the protein","volume":"96","author":"Munday","year":"2015","journal-title":"Molecular Microbiology"},{"key":"bib59","doi-asserted-by":"publisher","DOI":"10.3390\/tropicalmed5010014","article-title":"The drugs of sleeping sickness: their mechanisms of action and resistance, and a brief history","volume":"5","author":"P. De Koning","year":"2020","journal-title":"Tropical Medicine and Infectious Disease"},{"key":"bib60","doi-asserted-by":"publisher","first-page":"3559","DOI":"10.1063\/1.1590311","article-title":"Free energy calculation from steered molecular dynamics simulations using Jarzynski\u2019s equality","volume":"119","author":"Park","year":"2003","journal-title":"The Journal of Chemical Physics"},{"key":"bib61","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0003212","article-title":"Melarsoprol sensitivity profile of Trypanosoma brucei gambiense isolates from cured and relapsed sleeping sickness patients from the democratic republic of the Congo","volume":"8","author":"Pyana Pati","year":"2014","journal-title":"PLOS Neglected Tropical Diseases"},{"key":"bib62","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0008458","article-title":"Instability of aquaglyceroporin (AQP) 2 contributes to drug resistance in Trypanosoma brucei","volume":"14","author":"Quintana","year":"2020","journal-title":"PLOS Neglected Tropical Diseases"},{"key":"bib63","doi-asserted-by":"publisher","first-page":"890","DOI":"10.1128\/AAC.03958-14","article-title":"A new nonpolar N-hydroxy imidazoline lead compound with improved activity in a murine model of late-stage Trypanosoma brucei brucei infection is not cross-resistant with diamidines","volume":"59","author":"R\u00edos Mart\u00ednez","year":"2015","journal-title":"Antimicrobial Agents and Chemotherapy"},{"key":"bib64","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1038\/167147a0","article-title":"Acquired resistance to 'Melarsen', tryparsamide and amidines in pathogenic trypanosomes after treatment with 'Melarsen' alone","volume":"167","author":"Rollo","year":"1951","journal-title":"Nature"},{"key":"bib65","doi-asserted-by":"publisher","first-page":"4946","DOI":"10.1093\/nar\/gkq237","article-title":"Genome-wide analysis of mRNA abundance in two life-cycle stages of Trypanosoma brucei and identification of splicing and polyadenylation sites","volume":"38","author":"Siegel","year":"2010","journal-title":"Nucleic Acids Research"},{"key":"bib66","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1016\/j.molbiopara.2010.04.001","article-title":"Lipid metabolism in Trypanosoma brucei","volume":"172","author":"Smith","year":"2010","journal-title":"Molecular and Biochemical Parasitology"},{"key":"bib67","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1005436","article-title":"Pentamidine is not a permeant but a nanomolar inhibitor of the Trypanosoma brucei Aquaglyceroporin-2","volume":"12","author":"Song","year":"2016","journal-title":"PLOS Pathogens"},{"key":"bib68","doi-asserted-by":"publisher","first-page":"2606","DOI":"10.1021\/jm2014259","article-title":"Synthesis and structure-activity analysis of new phosphonium salts with potent activity against african trypanosomes","volume":"55","author":"Taladriz","year":"2012","journal-title":"Journal of Medicinal Chemistry"},{"key":"bib69","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1124\/mol.111.071555","article-title":"The diamidine diminazene aceturate is a substrate for the high-affinity pentamidine transporter: implications for the development of high resistance levels in trypanosomes","volume":"80","author":"Teka","year":"2011","journal-title":"Molecular Pharmacology"},{"key":"bib70","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1004942","article-title":"Specific cell targeting therapy bypasses drug resistance mechanisms in African trypanosomiasis","volume":"11","author":"Unciti-Broceta","year":"2015","journal-title":"PLOS Pathogens"},{"key":"bib71","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1002\/jcc.21367","article-title":"CHARMM general force field: a force field for drug\u2010like molecules compatible with the CHARMM all\u2010atom additive biological force field","volume":"31","author":"Vanommeslaeghe","year":"2010","journal-title":"Journal of Computational Chemistry"},{"key":"bib72","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1001204","article-title":"A molecular mechanism for eflornithine resistance in african trypanosomes","volume":"6","author":"Vincent","year":"2010","journal-title":"PLOS Pathogens"},{"key":"bib73","doi-asserted-by":"publisher","first-page":"26149","DOI":"10.1074\/jbc.M202835200","article-title":"Different substrate recognition motifs of human and trypanosome nucleobase transporters. selective uptake of purine antimetabolites","volume":"277","author":"Wallace","year":"2002","journal-title":"The Journal of Biological Chemistry"},{"key":"bib74","doi-asserted-by":"publisher","first-page":"2507","DOI":"10.1128\/AAC.00250-10","article-title":"Novel arylimidamides for treatment of visceral leishmaniasis","volume":"54","author":"Wang","year":"2010","journal-title":"Antimicrobial Agents and Chemotherapy"},{"key":"bib75","doi-asserted-by":"publisher","first-page":"2352","DOI":"10.1128\/AAC.01551-10","article-title":"Trypanocidal furamidine analogues: influence of pyridine nitrogens on trypanocidal activity, transport kinetics, and resistance patterns","volume":"55","author":"Ward","year":"2011","journal-title":"Antimicrobial Agents and Chemotherapy"},{"key":"bib76","doi-asserted-by":"publisher","first-page":"740","DOI":"10.1111\/j.1742-4658.2010.07993.x","article-title":"Requirement for asparagine in the aquaporin NPA sequence signature motifs for cation exclusion","volume":"278","author":"Wree","year":"2011","journal-title":"FEBS Journal"},{"key":"bib77","doi-asserted-by":"publisher","first-page":"2188","DOI":"10.1038\/emboj.2009.182","article-title":"Concerted action of two cation filters in the aquaporin water channel","volume":"28","author":"Wu","year":"2009","journal-title":"The EMBO Journal"},{"key":"bib78","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1016\/j.tips.2013.01.002","article-title":"Ligand action on sodium, potassium, and calcium channels: role of permeant ions","volume":"34","author":"Zhorov","year":"2013","journal-title":"Trends in Pharmacological Sciences"},{"key":"bib79","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1005236","article-title":"Modulation of the surface proteome through multiple ubiquitylation pathways in african trypanosomes","volume":"11","author":"Zoltner","year":"2015","journal-title":"PLOS Pathogens"},{"key":"bib80","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/j.mib.2016.08.005","article-title":"Exploiting the achilles' heel of membrane trafficking in trypanosomes","volume":"34","author":"Zoltner","year":"2016","journal-title":"Current Opinion in Microbiology"},{"key":"bib81","doi-asserted-by":"publisher","first-page":"8331","DOI":"10.1074\/jbc.RA120.012355","article-title":"Suramin exposure alters cellular metabolism and mitochondrial energy production in african trypanosomes","volume":"295","author":"Zoltner","year":"2020","journal-title":"Journal of Biological Chemistry"}],"container-title":["eLife"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/cdn.elifesciences.org\/articles\/56416\/elife-56416-v3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/cdn.elifesciences.org\/articles\/56416\/elife-56416-v3.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/elifesciences.org\/articles\/56416","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,11]],"date-time":"2023-10-11T21:07:05Z","timestamp":1697058425000},"score":1,"resource":{"primary":{"URL":"https:\/\/elifesciences.org\/articles\/56416"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,8,11]]},"references-count":81,"alternative-id":["10.7554\/eLife.56416"],"URL":"https:\/\/doi.org\/10.7554\/elife.56416","archive":["CLOCKSS"],"relation":{"has-review":[{"id-type":"doi","id":"10.7554\/eLife.56416.sa2","asserted-by":"object"},{"id-type":"doi","id":"10.7554\/eLife.56416.sa1","asserted-by":"object"},{"id-type":"doi","id":"10.3410\/f.738458391.793586034","asserted-by":"object"}],"has-preprint":[{"id-type":"doi","id":"10.1101\/2020.03.08.982751","asserted-by":"object"}]},"ISSN":["2050-084X"],"issn-type":[{"value":"2050-084X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,8,11]]},"article-number":"e56416"}}