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.
Organisations
- University of Glasgow (Lead Research Organisation)
- UNIVERSITY OF EDINBURGH (Collaboration)
- University of Glasgow (Collaboration)
- Food and Agricultural Organisation (FAO) (Collaboration)
- UNIVERSITY OF NOTTINGHAM (Collaboration)
- Eluceda Ltd (Collaboration)
- Bordeaux Segalen University (Collaboration)
- Boehringer Ingelheim (Collaboration)
Publications
Barrett MP
(2023)
The legacy of penicillin's first patient.
in Pharmacological research
Domagalska MA
(2023)
Drug resistance in Leishmania: does it really matter?
in Trends in parasitology
Koester DC
(2022)
Discovery of Novel Quinoline-Based Proteasome Inhibitors for Human African Trypanosomiasis (HAT).
in Journal of medicinal chemistry
Kovárová J
(2024)
The bloodstream form of Trypanosoma brucei displays non-canonical gluconeogenesis
in PLOS Neglected Tropical Diseases
Nastase AM
(2023)
Alignment of multiple metabolomics LC-MS datasets from disparate diseases to reveal fever-associated metabolites.
in PLoS neglected tropical diseases
Simwela NV
(2023)
A conserved metabolic signature associated with response to fast-acting anti-malarial agents.
in Microbiology spectrum
Steketee PC
(2023)
Anti-parasitic benzoxaboroles are ineffective against Theileria parva in vitro.
in International journal for parasitology. Drugs and drug resistance
Varghese S
(2024)
Novel aroyl guanidine anti-trypanosomal compounds that exert opposing effects on parasite energy metabolism.
in European journal of medicinal chemistry
| Description | At the University of Glasgow we have demonstrated that benzoxaborole compounds, of the valinate amide subclass, are exceptionally potent against Trypanosoma vivax as well as T. congolense (the two main causes of animal trypanosomosis). We have also shown activity aginst T. brucei and also T. evansi a parasite with global distribution. We have shown activity to involved inhibition of the enzyme CPSF3 (involved in RNA processing in these parasites). Resistance has been shown to be due to mutation to the TvCBP1 gene that encodes an enzyme responsible for cleaving the valinate amide prodrug. This is also the resistance mechanism seen for other trypanosome species |
| Exploitation Route | The finding that valinate amide benzoxaboroles are active against T. brucei, T. congolense and T. vivax (and T. evansi) means they may be developed as a next generation trypanocide for the treatment of the veterinary trypanosomiases. The data we have obtained on resistance, furthermore, enables evaluation of the risk of resistance forming and also the possibility of tests to survey for emerging resistance as a problem. |
| Sectors | Agriculture Food and Drink Pharmaceuticals and Medical Biotechnology |
| Description | Our findings have assisted the Global Alliance for Livestock and Veterinary Medicine (GALVmed) in developing a policy on development of new drugs for African animal trypanosomosis along with Industrial partners e.g. Boerhinger Ingelheim. The Food and Agriculture Organisation of the United Nations (FAO) has also been able to build this class of compound into future thinking on interventions. |
| First Year Of Impact | 2023 |
| Sector | Agriculture, Food and Drink,Pharmaceuticals and Medical Biotechnology |
| Impact Types | Cultural |
| 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/ |
| Description | Sceintific Advisory Board - Drugs for Neglected Diseases initiative 2023 |
| Geographic Reach | Multiple continents/international |
| Policy Influence Type | Participation in a guidance/advisory committee |
| Impact | The Drugs for Neglected Diseases initiative is developing new drugs for diseases afflicting the World's poorest people. In 2023 the drug fexinidazole received a positive opinion from the European Medicines Agency (EMA) for use in Rhodesiense human African trypanosomiasis. I Chaired the advisory board following the clinical trials that ultimately succeeded in receiving the EMA positive opinion. I also advise on their other programmes in leishmaniasis and trypanosomiasis (African and American) |
| URL | https://dndi.org/our-people/our-governance/ |
| Description | Workshop on Animal African trypanosomiasis in Arusha Tanzania |
| Geographic Reach | Multiple continents/international |
| Policy Influence Type | Participation in a guidance/advisory committee |
| URL | https://www.fao.org/paat/news-and-events/news/detail-events/en/c/1620473/ |
| Description | A portable device to detect counterfeit anti-parasitic drugs |
| Amount | £25,000 (GBP) |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 11/2023 |
| End | 01/2025 |
| 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 | An integrated approach to tackling drug resistance in livestock trypanosomes |
| Organisation | University of Edinburgh |
| Department | The Roslin Institute |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | University of Glasgow will test drug resistant parasites and seek mechanisms of resistance to veterinary trypanosomes (Barrett) and make mathematical models of drug resistance (Louise Matthews) |
| Collaborator Contribution | Project only just started |
| Impact | None to date |
| Start Year | 2019 |
| Description | Eluceda new devices to detect counterfeit trypanocidal drugs |
| Organisation | Eluceda Ltd |
| Country | United Kingdom |
| Sector | Private |
| PI Contribution | This collaboration aims to develop new electronic devices to distinguish real and counterfeit trypanocidal drugs. Since berenil (diminazene) and isometamidium carry positive charges they can be detected electrochemically using Eluceda's detection devices. We have been providing drug to optimise conditions and also blinded samples, and field samples, to determine efficacy of the device. |
| Collaborator Contribution | Eluceda has established conditions that are capable of the quantitative detection of trypanocidal drugs berenil (diminazene) and isometamidium. They have developed the tests and confirmed their utility using samples we have provided. |
| Impact | Multidisciplinary, multisectorial. Eluceda is a private company. A prototypical device capable of quantitative detection of berenil (diminazene) and isometamidium has been created. |
| Start Year | 2021 |
| Description | Food and Agriculture Organisation of the United Nations (FAO) |
| Organisation | Food and Agricultural Organisation (FAO) |
| Country | Italy |
| Sector | Charity/Non Profit |
| PI Contribution | Dr Federica Giordani, PDRA on our BBSRC grant (T. vivax) has been leading the writing of guidelines for the FAO on the treatment of the animal trypanosomoses. I have contributed a chapter on drug development to those guidelines. We are also contributing to the Progressive Control Pathway (PCP) for management and control of the animal trypanosomoses lead by FAO. |
| Collaborator Contribution | Dr Giuliano Cecchi at FAO is directing the production of treatment guidelines and has been actively engaged with Dr Giordani in their production. |
| Impact | Guidelines under preparation |
| Start Year | 2022 |
| Description | GalvMed Boerhinger Ingelheim development of benzoxaboroles for animal African trypanosomiasis |
| Organisation | Boehringer Ingelheim |
| Country | Germany |
| Sector | Private |
| PI Contribution | We have continued working on mode of action and resistance mechanisms of the benzoxaboroles considered for clinical veterinary development by BI. |
| Collaborator Contribution | We identified a serine carboxypeptidase involved in activating prodrugs in T. brucei and T. congolense. The compounds target the CPSF3 protein. Resistance emerges either when the peptidase genes are lost, or else when the target (CPSF3) gene copy number is increased. |
| Impact | Drug under development. |
| Start Year | 2019 |
| 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 | Glasgow Bordeaux |
| Organisation | Bordeaux Segalen University |
| Country | France |
| Sector | Academic/University |
| PI Contribution | We have measured the metabolome and transcriptome (to single cell level) of trypanosomes grown under differing conditions to understand the processes that drive metabolic shifts in these parasites when cultivated in different conditions (e.g. glucose vs glycerol). |
| Collaborator Contribution | Professor Bringaud's team in Bordeaux performed the initial experiments showing changes in metabolism of trypanosomes cultivated in different conditions and have proteomics data already. The French team provided cells and culture conditions. |
| Impact | To date we have gathered transcriptome and metabolome data currently under analysis. |
| Start Year | 2021 |
| Description | Glasgow Edinburgh |
| Organisation | University of Edinburgh |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | We have performed metabolomics and RNA sequencing analysis for our colleague on this grant Achim Schnaufer |
| Collaborator Contribution | Professor Schnaufer provided different cell lines under different growth conditions for metabolome and transcriptome analysis |
| Impact | Datasets generated, analysis not complete |
| Start Year | 2019 |
| Description | Glasgow Roslin institute collaboration |
| Organisation | University of Edinburgh |
| Department | The Roslin Institute |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | We have a strong collaboration with Roslin generating new culture media and selecting lines of parasite resistant to drugs in vitro. We are selecting lines in mice. We perform metabolomics analysis for the Roslin group. We are also (Professor Louise Matthews) generating mathematical models of disease. THe project also involves Dr Harriet Auty collecting filed isolates from Tanzania. We will assess these for genotype and drug resistance |
| Collaborator Contribution | Roslin institute have created drug resistant lines and sent cellular extracts and medium for metabolome analysis |
| Impact | Isometamidium resistant T. congolense selected in vitro and genome sequenced Isometamidium resistant T. congolense selected in vivo Benzoxaborole AN11736 resistant T. congolense selected in vitro. Drug resistance gene (TcoCBP1) discovered. Also for T. brucei Other Benzoxaborole resistant lines selected. |
| Start Year | 2019 |
| Description | Hariet Authy & Shauna Richards |
| Organisation | University of Glasgow |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | We provide support in helping identify and diagnose trypanosomes in the field. Also in assessing quality of drugs brought back from the field and input into likely resistance risk and mechanisms to various drugs |
| Collaborator Contribution | Hariet and Shauna work in Tanzania. They are collecting drug samples for us to test authenticity. They are collecting data on prevalence and species of trypanosome causing disease in Africa, as well as information on drug treatment which will go into building models of epidemiology of disease. |
| Impact | Hariet and Shuana have brought numerous samples of isometamidium and diminazene back to the UK from Tanzania and these will be tested for authenticty using LCMS and also used to evaluate the Eluceda device |
| Start Year | 2019 |
| Description | Liam Morrison: A new drug discovery pipeline for animal African trypanosomiasis |
| Organisation | University of Edinburgh |
| Department | The Roslin Institute |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Liam Morrison is a veterinary Parasitologist with expertise in the biology of veterinary trypanosomes. He is adding expertise in cultivation of trypanosomes of veterinary significance and understanding their genomic and metabolomic profiles with a view to drug discovery |
| Collaborator Contribution | Dr Morrison is adding expertise in cultivation of trypanosomes of veterinary significance and understanding their genomic and metabolomic profiles with a view to drug discovery |
| Impact | We have recently developed a new medium for the cultivation of Trypanosoma congolense to assist in drug screening. New genomic information is also assisting identification of drug targets |
| Start Year | 2008 |
| Description | Article about penicillin's first patient in the New Statesman magazine |
| Form Of Engagement Activity | A magazine, newsletter or online publication |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Public/other audiences |
| Results and Impact | Article outlining the story of penicillin's first patient, the visit of his daughter to his grave and the coming crisis in antibiotics due to AMR |
| Year(s) Of Engagement Activity | 2023 |
| URL | https://www.newstatesman.com/politics/health/2023/06/albert-alexander-legacy-penicillin-first-patien... |
| Description | International Workshop on Animal African trypanosomiasis in Arusha, Tanzania |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Study participants or study members |
| Results and Impact | We organised a three day meeting in Arusha Tanzania including scientists, veterinarians, funders and politicians plus representatives from the Food and Agriculture Organisation of the United Nations in order to update on the global situation regarding animal African trypanosomiasis and through a series of workshops formulate international policy on implementation of control measures. 120 participants gathered. |
| Year(s) Of Engagement Activity | 2023 |
| URL | https://www.fao.org/paat/news-and-events/news/detail-events/en/c/1620473/ |
| Description | Newspaper article and interview on penicillin's first patient |
| Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Public/other audiences |
| Results and Impact | I was interviewed by the Herald newspaper, along with the daughter of penicillin's first patient, outlining the story of penicillin, the tragedy of the loss of its first patient, the boom in antimicrobials and looming crisis in antimicrobial resistance |
| Year(s) Of Engagement Activity | 2023 |
| URL | https://www.heraldscotland.com/news/23592325.story-penicillin-told-world-congress-pharmacology/ |
| Description | Penicillin's first patient's daughter's visit to her father's grave |
| Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Public/other audiences |
| Results and Impact | As part of the visit to the UK I arranged for Sheila LeBlanc, the daughter of penicillin's first patient, we were interviewed by BBC news at the grave yard in Newbury, Berkshire where Constable Albert Alexander is buried. The interview was part of a news feature covering the story of Constable Alexander, his treatment with penicillin and the ensuing revolution in antimicrobial therapy that followed the discovery. |
| Year(s) Of Engagement Activity | 2023 |
| 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/ |
| Description | Talk on penicillin's first patient at the World Congress of Pharmacology |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | I organised a scientific session on the antibiotic resistance crisis at the World congress of Pharmacology. As part of the symposium a pubic engagement lecture was included at which I gave an outline on the history of penicillin and the fate of its first patient. |
| Year(s) Of Engagement Activity | 2023 |
| URL | https://wcp2023.org/events/antibiotics-solving-the-crisis/ |
| Description | Talk to Wootton village history society |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Public/other audiences |
| Results and Impact | As part of the visit, I arranged, of the daughter of penicillin's first patient to the UK I spoke on the history of penicillin to the Wootton history society. Wootton is the village from which Albert Alexander, the policeman first treated with penicillin came. |
| Year(s) Of Engagement Activity | 2023 |
| URL | https://www.newstatesman.com/politics/health/2023/06/albert-alexander-legacy-penicillin-first-patien... |
| Description | Talk to school. "The next pandemic" |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Schools |
| Results and Impact | A talk to sixth formers at the High School of Glasgow on the persistent threat of infectious diseases, contextualised around the Covid19 pandemic |
| Year(s) Of Engagement Activity | 2023 |