Metabolism and drug resistance probed with new genetic tools in the neglected animal pathogen Trypanosoma vivax.
Lead Research Organisation:
University of Glasgow
Department Name: College of Medical, Veterinary, Life Sci
Abstract
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Technical Summary
Trypanosoma vivax is one of the main causes of Animal African Trypanosomiasis, but is sorely neglected despite its substantial impact. This project will bridge the critical knowledge and capability gaps in order to shift paradigms for basic and applied research on this important pathogen. The project will build on the experience of the applicants, and the industrial partner, the Global Alliance for Livestock Veterinary Medicines (GALVmed), to generate new knowledge on key areas of T. vivax biology and develop a laboratory toolkit for in vitro culture and genetic transformation, through a series of integrated aims. We will comprehensively characterise the metabolism of bloodstream-form T. vivax using RNAseq and LC-MS/GC-MS, enabling the production of a genome-scale model of metabolism. Predictions will be validated in genetic mutants or chemical inhibition of key metabolic steps. In parallel, the T. vivax surface proteome will be defined to identify proteins expected to be involved in metabolite and drug transport. Resistance induced both in vivo and in vitro to three drugs - the widely used diminazene aceturate and isometamidium chloride, and a benzoxaborole in clinical development - will be used in combination with data on parasite metabolism and surface proteome to identify mechanisms of drug uptake and resistance. These outputs will provide novel and foundational information on how T. vivax interacts with its environment, and particularly how it responds to exposure to drugs. Finally, we will generate laboratory capabilities to transform the ability to work meaningfully with T. vivax. Building upon the applicants' expertise with related trypanosomes, we will use the data generated to design culture medium that will support the growth of bloodstream-form T. vivax, and will generate a toolkit for functional genetics in this important parasite.
Publications
Koester DC
(2022)
Discovery of Novel Quinoline-Based Proteasome Inhibitors for Human African Trypanosomiasis (HAT).
in Journal of medicinal chemistry
Simwela NV
(2023)
A conserved metabolic signature associated with response to fast-acting anti-malarial agents.
in Microbiology spectrum
Nastase AM
(2023)
Alignment of multiple metabolomics LC-MS datasets from disparate diseases to reveal fever-associated metabolites.
in PLoS neglected tropical diseases
Domagalska MA
(2023)
Drug resistance in Leishmania: does it really matter?
in Trends in parasitology
Steketee PC
(2023)
Anti-parasitic benzoxaboroles are ineffective against Theileria parva in vitro.
in International journal for parasitology. Drugs and drug resistance
Barrett M
(2023)
The legacy of penicillin's first patient
in Pharmacological Research
Kovárová J
(2024)
The bloodstream form of Trypanosoma brucei displays non-canonical gluconeogenesis
in PLOS Neglected Tropical Diseases
Varghese S
(2024)
Novel aroyl guanidine anti-trypanosomal compounds that exert opposing effects on parasite energy metabolism.
in European journal of medicinal chemistry
Description | Federica Giordani contributions to the Food and Agriculture Organisation of the United Nations (FAO) |
Geographic Reach | Africa |
Policy Influence Type | Participation in a guidance/advisory committee |
Description | Membership of the Drugs for Neglected Diseases initiative (DNDi) Scientific Advisory Committee |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Participation in a guidance/advisory committee |
Impact | I provide advice on programmes in drug discovery against Neglected Tropical Diseases for DNDi, the world's leading organisation in drug development for diseases of the world's poorest people |
URL | https://dndi.org/our-people/mike-barrett/ |
Title | A model of emergence and transmission of antimicrobial resistance in African animal trypanosomiasis |
Description | This model has been constructed as part of the ongoing, multi-institutional project entitled Combatting African Animal Trypanosomiasis (COMBAAT). The key aims of the model are to understand the means by which antimicrobial resistance (AMR) emerges in response to treatment and prophylaxis, how this spreads throughout the population, and what role wildlife play in the maintinence or loss of this AMR. |
Type Of Material | Computer model/algorithm |
Year Produced | 2022 |
Provided To Others? | Yes |
Impact | The model enables farmers, vets and policy makers to consider the best approach to the control of animal African trypanosomiasis in given scenarios in the context of risks of drug resistance emerging. |
URL | https://github.com/shaunkeegan/AAT_AMR_main |
Title | Metabolomics dataset - Novel Minor Groove Binders cure animal African trypanosomiasis in an in vivo mouse model |
Description | Metabolomics dataset at Metabolights |
Type Of Material | Database/Collection of data |
Year Produced | 2019 |
Provided To Others? | Yes |
Impact | Indication of drug mode of action |
URL | https://www.ebi.ac.uk/metabolights/MTBLS464 |
Description | Glasgow - Nottingham collaboration |
Organisation | University of Nottingham |
Department | School of Life Sciences |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Investigating post-translational modifications and epigenetics of trypanosomatids |
Collaborator Contribution | Still in the phase of methods development |
Impact | Still developing methods. Several face to face and online conferences |
Start Year | 2019 |
Description | SCOTLAND - RHEINLAND-PFALZ LIFE SCIENCES AND BIOTECHNOLOGY CONFERENCE |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Policymakers/politicians |
Results and Impact | Conference aiming to bring researchers in the Life Sciences in Scotlnd and the Rhineland closer together to explore collaborative opportunities |
Year(s) Of Engagement Activity | 2022,2023 |
URL | https://sulsa.ac.uk/first-scottish-rheinland-pfalz-life-sciences-and-biotechnology-conference/ |