{"database":"MetaboLights","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Tabular":["ftp://ftp.ebi.ac.uk/pub/databases/metabolights/studies/public/MTBLS882/m_mgb234_metabolite_profiling_mass_spectrometry_v2_maf.tsv","ftp://ftp.ebi.ac.uk/pub/databases/metabolights/studies/public/MTBLS882/m_mgb234_metabolite_profiling_mass_spectrometry-1_v2_maf.tsv"],"Txt":["ftp://ftp.ebi.ac.uk/pub/databases/metabolights/studies/public/MTBLS882/a_mgb234_metabolite_profiling_mass_spectrometry-1.txt","ftp://ftp.ebi.ac.uk/pub/databases/metabolights/studies/public/MTBLS882/i_Investigation.txt","ftp://ftp.ebi.ac.uk/pub/databases/metabolights/studies/public/MTBLS882/s_MGB234.txt","ftp://ftp.ebi.ac.uk/pub/databases/metabolights/studies/public/MTBLS882/a_mgb234_metabolite_profiling_mass_spectrometry.txt"],"Other":["ftp://ftp.ebi.ac.uk/pub/databases/metabolights/studies/public/MTBLS882/DERIVED_FILES","ftp://ftp.ebi.ac.uk/pub/databases/metabolights/studies/public/MTBLS882","ftp://ftp.ebi.ac.uk/pub/databases/metabolights/studies/public/MTBLS882/files-all.json","ftp://ftp.ebi.ac.uk/pub/databases/metabolights/studies/public/MTBLS882/RAW_FILES"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"submitter":["Federica Giordani"],"repository":["MetaboLights"],"study_status":["Public"],"ptm_modification":[""],"instrument_platform":["Liquid Chromatography MS - Alternating (LC-MS (Alternating))"],"mass_spec_protocol":["
Q-Exactive Orbitrap mass spectrometer (Thermo Fisher Scientific) data were acquired using the following settings: resolution 70,000, AGC 1e6, m/z range 70-1050, sheath gas 40, auxiliary gas 5, sweep gas 1 unit, probe temperature 150 °C, capillary temperature 320 °C. Spray voltages were the following: for positive mode ionisation, source voltage +3.8 kV, S-Lens RF Level 30.00, S-Lens Voltage -25.00 (V), Skimmer Voltage -15.00 (V), Inject Flatopole Offset -8.00 (V), Bent Flatapole DC -6.00 (V). For negative mode ionisation: source voltage -3.8 kV. Mass calibration was performed for each polarity immediately before each analysis batch.
"],"chromatography_protocol":["Samples were analysed by hydrophilic interaction liquid chromatography (HILIC)–mass spectrometry on a Q-Exactive Orbitrap mass spectrometer (Thermo Fisher Scientific) in both positive and negative modes (switching mode), coupled to a HPLC system (Dionex) with a ZIC-pHILIC column (150 mm × 4.6 mm, 5 μm column, Merck Sequant). HPLC mobile phase A was 20 mM ammonium carbonate in water, and mobile phase B was 100% acetonitrile. The column was maintained at 20 °C and samples were eluted with a linear gradient from 80% B to 20% B over 24 min, followed by 8 min wash with 5% B and 8 min re-equilibration with 80% B, at the flow rate of 300 µl/min. The injection volume was 10 µl.
"],"publication":["Novel Minor Groove Binders cure animal African trypanosomiasis in an in vivo mouse model. 10.1021/acs.jmedchem.8b01847. PMID:30763102"],"submitter_affiliation":["University of Glasgow"],"Organism":["blank","Trypanosoma brucei"],"technology_type":["mass spectrometry"],"disease":[""],"extraction_protocol":["At the end of the treatment time, 1 x 10^8 parasites per sample were rapidly cooled in a dry ice/ethanol bath to 4 ⁰C. Pellets were collected and washed once in 1 X PBS and then extracted by shaking in 200 µL HPLC grade chloroform:methanol:water (1:3:1 volume ration) on ice for 1 h. Centrifuged supernatant was stored at -80 ⁰C under argon.
"],"full_dataset_link":["https://www.ebi.ac.uk/metabolights/MTBLS882"],"author":["Harry de Koning. University of Glasgow. Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK. Harry.De-Koning@glasgow.ac.uk. (+44) 1413303753.","Abedawn Khalaf. University of Strathclyde. Department of Pure and Applied Chemistry, WestCHEM, University of Strathclyde, Glasgow G1 1XL, UK. abedawnkhalaf@yahoo.co.uk.","Federica Giordani. University of Glasgow. Wellcome Centre for Integrative Parasitology, Institute of Infection, Immunity and Inflammation, & Glasgow Polyomics, University of Glasgow, University Place, Glasgow, G12 8TA, UK. federica.giordani@glasgow.ac.uk. (+44) 0141 330 5276.","Colin Suckling. University of Strathclyde. Department of Pure and Applied Chemistry, WestCHEM, University of Strathclyde, Glasgow G1 1XL, UK. c.j.suckling@strath.ac.uk. (+44) 0141 548 2271.","Kirsten Gillingwater. Swiss Tropical and Public Health Institute. Parasite Chemotherapy, Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel 4051, Switzerland. kgillingwater@dndi.org.","Jane Munday. University of Glasgow. Wellcome Centre for Integrative Parasitology, Institute of Infection, Immunity and Inflammation, & Glasgow Polyomics, University of Glasgow, University Place, Glasgow, G12 8TA, UK. Jane.Munday@glasgow.ac.uk. (+44) 1413304426.","Michael Barrett. University of Glasgow. Wellcome Centre for Integrative Parasitology, Institute of Infection, Immunity and Inflammation, & Glasgow Polyomics, University of Glasgow, University Place, Glasgow, G12 8TA, UK. Michael.Barrett@glasgow.ac.uk. (+44) 1413306904.","Fraser Scott. University of Huddersfield. Department of Biological and Geographical Sciences, School of Applied Sciences, University of Huddersfield, Huddersfield HD1 3DH, UK. f.scott@hud.ac.uk. (+44) 01484 473694."],"data_transformation_protocol":["Untargeted peak-picking and peak matching from raw LC-MS data were obtained using XCMS and mzMatch respectively. Metabolite identification and relative quantitation was performed using IDEOM interface, by matching accurate masses and retention times of authentic standards or, when standards were not available, by using predicted retention times. p-values were adjusted for multiple testing using the Benjamini-Hochberg method. Data were also filtered, aligned and annotated using the Orbiwarp algorithm in PiMP (http://polyomics.mvls.gla.ac.uk/).
"],"study_factor":["Treatment","Replicate"],"submitter_email":[""],"sample_collection_protocol":["Bloodstream form T. b. brucei lister 427 were treated with 5xEC50 (0.8 µM) of compound 7 (S-MGB-234) or vehicle DMSO control (DMSO) in HMI-11 for 8 h at 37 ºC. 1 x 10^8 parasites per sample were collected for extraction. 4 biological replicates were prepared.
"],"omics_type":["Metabolomics"],"study_design":["Mode of Action","ultra-performance liquid chromatography-mass spectrometry","Glasgow Polyomics","DNA Minor Groove Binding","tandem mass spectrometry","drug resistance","Antiprotozoal Agent","Strathclyde-minor groove binders"],"curator_keywords":["ultra-performance liquid chromatography-mass spectrometry","Mode of Action","Glasgow Polyomics","DNA Minor Groove Binding","tandem mass spectrometry","drug resistance","Antiprotozoal Agent","Strathclyde-minor groove binders"],"Organism Part":["bloodstream form","blank"],"metabolite_id_protocol":["Metabolite identification and relative quantitation was performed using the IDEOM interface[1], by matching accurate masses and retention times of authentic standards or, when standards were not available, by using predicted retention times. A retention time window of 30 seconds and a ppm error of 3 to match masses and retention times to authentic standards were used. The putative metabolite list obtained by IDEOM was manually checked and filtered based on peak intensity and shape. Statistical analysis of the resulting list was performed using MetaboAnalyst 3.0 following log transformation of the data. Fragmentation patterns were integrated in the analysis using the Polyomics integrated Metabolomics Pipeline, PiMP (http://polyomics.mvsl.gla.ac.uk/).
Ref:
[1] Creek DJ, Jankevics A, Burgess KE, Breitling R, Barrett MP. IDEOM: an Excel interface for analysis of LC-MS-based metabolomics data. Bioinformatics. 2012 Apr 1;28(7):1048-9. doi:10.1093/bioinformatics/bts069. Epub 2012 Feb 4. PMID:22308147
"],"metabolite_name":["Creatinine","Deoxyuridine","Dethiobiotin","NG,NG-Dimethyl-L-arginine","Pyridoxine","dAMP","Cytidine","N6-Acetyl-L-lysine","D-Lysine","dCTP","Uridine","5-6-Dihydrouridine","Hypoxanthine","dUMP","Cytosine","Pyridoxamine"],"pubmed_abstract":["Animal African trypanosomiasis (AAT) is a significant socioeconomic burden for sub-Saharan Africa because of its huge impact on livestock health. Existing therapies including those based on minor groove binders (MGBs), such as the diamidines, which have been used for decades, have now lost efficacy in some places because of the emergence of resistant parasites. Consequently, the need for new chemotherapies is urgent. Here, we describe a structurally distinct class of MGBs, Strathclyde MGBs (S-MGBs), which display excellent in vitro activities against the principal causative organisms of AAT: Trypanosoma congolense, and Trypanosoma vivax. We also show the cure of T. congolense-infected mice by a number of these compounds. In particular, we identify S-MGB-234, compound 7, as curative by using two applications of 50 mg/kg intraperitoneally. Crucially, we demonstrate that S-MGBs do not show cross-resistance with the current diamidine drugs and are not internalized via the transporters used by diamidines. This study demonstrates that S-MGBs have significant potential as novel therapeutic agents for AAT."],"pubmed_title":["Novel Minor Groove Binders Cure Animal African Trypanosomiasis in an in Vivo Mouse Model."],"pubmed_authors":["Giordani Federica F, Khalaf Abedawn I AI, Gillingwater Kirsten K, Munday Jane C JC, de Koning Harry P HP, Suckling Colin J CJ, Barrett Michael P MP, Scott Fraser J FJ"],"description_synonyms":["Trypanosoma congolenses, 3.4.22.-, multi-cellular organism, 2-oxoglutarate-glutamate aminotransferase activity, insensitive, Laboratory, glutamic--oxaloacetic transaminase activity, Mus domesticus, number, Alpha-1-antiproteinase, mini-ICE, CSMF, CASP-14, nucleus geniculatus medialis, Yperite, Ximpact, Normalcies, House Mouse, African trypanosomiasis, Serpin A1b, Serpin A1a, glutamic-oxalacetic transaminase activity, Trypanosoma, Tier, Africa, vivax, House, L-aspartate-alpha-ketoglutarate transaminase activity., concavities, Trypanosoma (Nannomonas) congolense, resistance, A1A, 1, Mus musculus domesticus, aspartic aminotransferase activity, AAT, Mustard gas, 1'-thiobis(2-chloroethane), animal, L-aspartate-2-oxoglutarate aminotransferase activity, Mice, Normalities, aspartic acid aminotransferase activity, average, study, glutamate-oxalacetate aminotransferase activity, glutamate oxaloacetate transaminase activity, fossa, corpus geniculatum mediale, AI573420, Swiss, Iprit, anon-WO0118547.126, Swiss Mice, metazoa, number of, PI1, growl, oxaloacetate transferase activity, Subsaharan Africa, concavity, A1AT, aspartyl aminotransferase activity, bis(2-chloroethyl) sulphide, Lost, medial geniculate nuclei, NOR-1, drugs, CG14648, Trypanosoma vivaxs, glutamic oxalic transaminase activity, medicine, 1-chloro-2-[(2-chloroethyl)sulfanyl]ethane, oxaloacetate-aspartate aminotransferase activity, mustard gas, has or lacks parts of type, DmelCG14648, HAT, Livestocks, PRO2275, congolense, alpha1AT, sulfur mustard, sleeping sickness, nuclei corporis geniculati medialis, Individual Health, NOR1, Nor1, medial geniculate nucleus, aspartate:2-oxoglutarate aminotransferase activity, Growl, CHN, aspartate-2-oxoglutarate transaminase activity, glutamic-aspartic aminotransferase activity, 1-chloro-2-[(2-chloroethyl)thio]ethane, body, African sleeping sickness, animalia, Sub-Saharan Africa, aspartate transaminase activity, mouse, Serine protease inhibitor A1b, glutamic--aspartic transaminase activity, Serine protease inhibitor A1a, internal geniculate body, whole body, L-aspartate transaminase activity, extra or missing physical or functional parts, Normalcy, bis(2-chloroethyl) sulfide, impact-a, nev, mereological quality, organism, bis(2-chloroethyl)sulfane, AspT, Mus, African Trypanosomiasis, fossae, Mini-ICE, L-aspartic aminotransferase activity, aspartate alpha-ketoglutarate transaminase activity, Africam sleeping sickness, Individual, human African trypanosomiasis, Sub-Saharan, cell surface groove, medial geniculate complex, L-aspartate-2-oxoglutarate-transaminase activity, corpus geniculatus medialis, transaminase A activity, Mus musculus, furrow, Alpha-1 protease inhibitor 2, Alpha-1 protease inhibitor 1, groove, whole organism, resistant, distinct, Caspase-14 subunit p10, MINOR, nucleus corporis geniculati medialis, Normality, mice, Swiss Mouse, depressions, Senfgas, glutamate-oxalate transaminase activity, House Mice, Serine protease inhibitor 1-2, Caspase-14 subunit p19, Serine protease inhibitor 1-1, MICE, GOT (enzyme), mg/kg, Laboratory Mice, domesticus, medial geniculate complex of dorsal thalamus, aspartate aminotransferase activity, Health, Parasite, MGB, Koerper, cardinality, TEC, L-aspartate-2-ketoglutarate aminotransferase activity, Mouse, MGN, PI, E430016J11Rik, Minor, depression, Laboratory Mouse, RWDD5, L-aspartate-alpha-ketoglutarate transaminase activity"],"pubmed_title_synonyms":["mice., furrow, NOR1, Nor1, groove, multi-cellular organism, CHN, whole organism, fossa, MINOR, AI573420, body, African sleeping sickness, animalia, mouse, depressions, whole body, CSMF, metazoa, concavity, African trypanosomiasis, organism, NOR-1, Tier, Mus, African Trypanosomiasis, concavities, fossae, Koerper, TEC, Mouse, Africam sleeping sickness, house mouse, animal, human African trypanosomiasis, HAT, Minor, depression, cell surface groove, sleeping sickness"],"name_synonyms":["mice., furrow, NOR1, Nor1, groove, multi-cellular organism, CHN, whole organism, fossa, MINOR, AI573420, body, African sleeping sickness, animalia, mouse, depressions, whole body, CSMF, metazoa, concavity, African trypanosomiasis, organism, NOR-1, Tier, Mus, African Trypanosomiasis, concavities, fossae, Koerper, TEC, Mouse, Africam sleeping sickness, house mouse, animal, human African trypanosomiasis, HAT, Minor, depression, cell surface groove, sleeping sickness"],"pubmed_abstract_synonyms":["Trypanosoma congolenses, 3.4.22.-, multi-cellular organism, 2-oxoglutarate-glutamate aminotransferase activity, insensitive, Laboratory, glutamic--oxaloacetic transaminase activity, Mus domesticus, number, Alpha-1-antiproteinase, mini-ICE, CSMF, CASP-14, nucleus geniculatus medialis, Yperite, Ximpact, Normalcies, House Mouse, African trypanosomiasis, Serpin A1b, Serpin A1a, glutamic-oxalacetic transaminase activity, Trypanosoma, Tier, Africa, vivax, House, L-aspartate-alpha-ketoglutarate transaminase activity., concavities, Trypanosoma (Nannomonas) congolense, resistance, A1A, 1, Mus musculus domesticus, aspartic aminotransferase activity, AAT, Mustard gas, 1'-thiobis(2-chloroethane), animal, L-aspartate-2-oxoglutarate aminotransferase activity, Mice, Normalities, aspartic acid aminotransferase activity, average, study, glutamate-oxalacetate aminotransferase activity, glutamate oxaloacetate transaminase activity, fossa, corpus geniculatum mediale, AI573420, Swiss, Iprit, anon-WO0118547.126, Swiss Mice, metazoa, number of, PI1, growl, oxaloacetate transferase activity, Subsaharan Africa, concavity, A1AT, aspartyl aminotransferase activity, bis(2-chloroethyl) sulphide, Lost, medial geniculate nuclei, NOR-1, drugs, CG14648, Trypanosoma vivaxs, glutamic oxalic transaminase activity, medicine, 1-chloro-2-[(2-chloroethyl)sulfanyl]ethane, oxaloacetate-aspartate aminotransferase activity, mustard gas, has or lacks parts of type, DmelCG14648, HAT, Livestocks, PRO2275, congolense, alpha1AT, sulfur mustard, sleeping sickness, nuclei corporis geniculati medialis, Individual Health, NOR1, Nor1, medial geniculate nucleus, aspartate:2-oxoglutarate aminotransferase activity, Growl, CHN, aspartate-2-oxoglutarate transaminase activity, glutamic-aspartic aminotransferase activity, 1-chloro-2-[(2-chloroethyl)thio]ethane, body, African sleeping sickness, animalia, Sub-Saharan Africa, aspartate transaminase activity, mouse, Serine protease inhibitor A1b, glutamic--aspartic transaminase activity, Serine protease inhibitor A1a, internal geniculate body, whole body, L-aspartate transaminase activity, extra or missing physical or functional parts, Normalcy, bis(2-chloroethyl) sulfide, impact-a, nev, mereological quality, organism, bis(2-chloroethyl)sulfane, AspT, Mus, African Trypanosomiasis, fossae, Mini-ICE, L-aspartic aminotransferase activity, aspartate alpha-ketoglutarate transaminase activity, Africam sleeping sickness, Individual, human African trypanosomiasis, Sub-Saharan, cell surface groove, medial geniculate complex, L-aspartate-2-oxoglutarate-transaminase activity, corpus geniculatus medialis, transaminase A activity, Mus musculus, furrow, Alpha-1 protease inhibitor 2, Alpha-1 protease inhibitor 1, groove, whole organism, resistant, distinct, Caspase-14 subunit p10, MINOR, nucleus corporis geniculati medialis, Normality, mice, Swiss Mouse, depressions, Senfgas, glutamate-oxalate transaminase activity, House Mice, Serine protease inhibitor 1-2, Caspase-14 subunit p19, Serine protease inhibitor 1-1, MICE, GOT (enzyme), mg/kg, Laboratory Mice, domesticus, medial geniculate complex of dorsal thalamus, aspartate aminotransferase activity, Health, Parasite, MGB, Koerper, cardinality, TEC, L-aspartate-2-ketoglutarate aminotransferase activity, Mouse, MGN, PI, E430016J11Rik, Minor, depression, Laboratory Mouse, RWDD5, L-aspartate-alpha-ketoglutarate transaminase activity"],"citation_count_scaled":["0.0"],"download_count_scaled":["0.0"],"normalized_connections":["0.0"],"reanalysis_count_scaled":["0.0"],"view_count_scaled":["0.0"],"additional_accession":[]},"is_claimable":false,"name":"Novel Minor Groove Binders cure animal African trypanosomiasis in an in vivo mouse model","description":"Animal African trypanosomiasis (AAT) is a significant socioeconomic burden for sub-Saharan Africa because of its huge impact on livestock health. Existing therapies including those based on minor groove binders (MGBs), such as the diamidines, which have been used for decades, have now lost efficacy in some places because of the emergence of resistant parasites. Consequently, the need for new chemotherapies is urgent. Here, we describe a structurally distinct class of MGBs, Strathclyde MGBs (S-MGBs), which display excellent in vitro activities against the principal causative organisms of AAT: Trypanosoma congolense, and Trypanosoma vivax. We also show the cure of T. congolense-infected mice by a number of these compounds. In particular, we identify S-MGB-234, compound 7, as curative by using two applications of 50 mg/kg intraperitoneally. Crucially, we demonstrate that S-MGBs do not show cross-resistance with the current diamidine drugs and are not internalized via the transporters used by diamidines. This study demonstrates that S-MGBs have significant potential as novel therapeutic agents for AAT.","dates":{"publication":"2022-01-18","submission":"2019-03-12"},"accession":"MTBLS882","cross_references":{"MetaboLights":["MTBLC16691","MTBLC16040","MTBLC17562","MTBLC16450","MTBLC17622","MTBLC17368","MTBLC16410","MTBLC17752","MTBLC16311","MTBLC16855","MTBLC17713","MTBLC16737","MTBLC16704","MTBLC16709","MTBLC17929","MTBLC23774"],"pubmed":["30763102"],"ChEBI":["CHEBI:16709","CHEBI:17929","CHEBI:16855","CHEBI:16737","CHEBI:16704","CHEBI:17713","CHEBI:17368","CHEBI:17622","CHEBI:17752","CHEBI:17562","CHEBI:16311","CHEBI:16410","CHEBI:16040","CHEBI:16450","CHEBI:23774","CHEBI:16691"]}}