Benzoxaborole treatment perturbs S-adenosyl-L-methionine metabolism in Trypanosoma brucei

PLoS Neglected Tropical Diseases
Pieter C SteketeeMichael P Barrett

Abstract

The parasitic protozoan Trypanosoma brucei causes Human African Trypanosomiasis and Nagana in other mammals. These diseases present a major socio-economic burden to large areas of sub-Saharan Africa. Current therapies involve complex and toxic regimens, which can lead to fatal side-effects. In addition, there is emerging evidence for drug resistance. AN5568 (SCYX-7158) is a novel benzoxaborole class compound that has been selected as a lead compound for the treatment of HAT, and has demonstrated effective clearance of both early and late stage trypanosomiasis in vivo. The compound is currently awaiting phase III clinical trials and could lead to a novel oral therapeutic for the treatment of HAT. However, the mode of action of AN5568 in T. brucei is unknown. This study aimed to investigate the mode of action of AN5568 against T. brucei, using a combination of molecular and metabolomics-based approaches.Treatment of blood-stage trypanosomes with AN5568 led to significant perturbations in parasite metabolism. In particular, elevated levels of metabolites involved in the metabolism of S-adenosyl-L-methionine, an essential methyl group donor, were found. Further comparative metabolomic analyses using an S-adenosyl-L-methionine-depen...Continue Reading

References

Apr 1, 1986·Parasitology·G S LamontG A Cross
May 1, 1983·The Journal of Antimicrobial Chemotherapy·M J HallD Westmacott
Jan 1, 1994·Advances in Parasitology·J Pépin, F Milord
Feb 13, 2001·Molecular and Biochemical Parasitology·M P Hasne, M P Barrett
Jun 27, 2003·Trends in Biochemical Sciences·Heidi L SchubertXiaodong Cheng
Dec 10, 2003·Current Opinion in Microbiology·Paul G McKean
Oct 3, 2006·Cellular and Molecular Life Sciences : CMLS·C Qian, M-M Zhou
Jun 22, 2007·Physiology & Behavior·Willias MasochaKrister Kristensson
May 15, 2008·Nucleic Acids Research·Shujiro OkudaMinoru Kanehisa
Dec 25, 2008·Proceedings of the National Academy of Sciences of the United States of America·Mathurin KoffiVincent Jamonneau
Oct 22, 2009·Nucleic Acids Research·Martin AslettHaiming Wang
Oct 12, 2010·Molecular & Cellular Proteomics : MCP·Tanya C Petrossian, Steven G Clarke
Mar 16, 2011·Analytical Chemistry·Richard A ScheltemaRainer Breitling
Jul 9, 2011·PLoS Neglected Tropical Diseases·Robert T JacobsRobert Don
Oct 1, 2011·Future Microbiology·Michael P BarrettEnock Matovu
Feb 7, 2012·Bioinformatics·Darren J CreekMichael P Barrett
May 9, 2012·PLoS Neglected Tropical Diseases·Isabel M VincentMichael P Barrett
Jun 30, 2012·Nature Methods·Johannes SchindelinAlbert Cardona
Oct 12, 2012·Nature Biotechnology·Matthew C ChambersParag Mallick
Nov 10, 2012·British Medical Bulletin·Michael P Barrett, Simon L Croft
Jan 9, 2013·Antimicrobial Agents and Chemotherapy·Vincent HernandezJacob J Plattner
Feb 16, 2013·Bioorganic & Medicinal Chemistry Letters·Tsutomu AkamaYvonne R Freund
Apr 11, 2013·Antimicrobial Agents and Chemotherapy·Darren J CreekMichael P Barrett
Jul 9, 2013·Handbook of Clinical Neurology·Veerle LejonJosé Ramon Franco
Nov 30, 2013·Nucleic Acids Research·Robert D FinnMarco Punta
Jan 24, 2014·Bioinformatics·Philip JonesSarah Hunter
May 24, 2014·PLoS Neglected Tropical Diseases·Andrea TrochineCarlos Robello
Jun 6, 2014·ACS Medicinal Chemistry Letters·Kanchan DevkotaRasmus Prætorius Clausen
Aug 15, 2014·Drugs·Anthony Markham
Sep 25, 2014·The Journal of Biological Chemistry·Yun WangPhilip A Cole
Oct 11, 2014·Nucleic Acids Research·Ivica LetunicPeer Bork

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Citations

Sep 27, 2018·PLoS Pathogens·Daniela BegoloChristine Clayton
Feb 11, 2020·Current Pharmaceutical Design·Vasiliki PardaliGrigoris Zoidis
Dec 18, 2018·Frontiers in Microbiology·Sanjay VarikutiAbhay R Satoskar
Sep 7, 2018·Proceedings of the National Academy of Sciences of the United States of America·Richard J WallDavid Horn
Feb 26, 2020·Tropical Medicine and Infectious Disease·Emily A DickieMichael P Barrett
Jul 1, 2020·Microorganisms·Magali Van den KerkhofGuy Caljon
Aug 31, 2019·Future Medicinal Chemistry·Glaécia An PereiraRafaela S Ferreira
Nov 4, 2020·PLoS Pathogens·Federica GiordaniMichael P Barrett
Jan 30, 2021·Molecular Microbiology·Suellen Rodrigues MaranNilmar Silvio Moretti
Feb 3, 2021·Infection and Immunity·Adwaita R Parab, Laura-Isobel McCall
Nov 10, 2021·PLoS Neglected Tropical Diseases·Pieter C SteketeeMichael P Barrett

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Methods Mentioned

BETA
fluorescence microscopy
PCA

Software Mentioned

Ideom
R
Metacyc
mzMatch
GraphPad Prism
SPSS
Excel
XCMS
TriTrypDB
Fiji

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African Trypanosomiasis

African trypanosomiasis, also known as sleeping sickness, is an insect-borne parasitic disease of humans and other animals. It is caused by protozoa of the species Trypanosoma brucei and almost invariably progresses to death unless treated. Discover the latest research on African trypanosomiasis here.