Bridging epigenetics, metabolism and cell cycle in pathogenic trypanosomatids
Lead Research Organisation:
University of Glasgow
Department Name: College of Medical, Veterinary, Life Sci
Abstract
We propose to bring together a group of researchers across the UK and in Sao Paulo to share expertise that will allow us to understand the biology of parasites that cause neglected tropical diseases and improve our ability to intervene against them. Disease-causing microbes remain a major problem for health the world over. This is seen disproportionately in tropical countries, were a combination of environmental factors (e.g. climatic conditions supporting the propagation of insects that can transmit disease) and relatively scarce economic resource ensure the maintenance of infectious disease. Parts of rural Brazil, like other areas in Latin America, suffer from diseases caused by parasitic protozoa, which are single-celled organisms. One parasite, Trypanosoma cruzi, causes Chagas disease, affecting several million people across Latin America. Closely-related parasites, belonging to the genus Leishmania, cause a range of diseases called the leishmaniases in many parts of the world. Chagas disease is transmitted by triatomine bugs that suck the blood of mammals including humans and in the process defecate upon their victims. Parasites in the faeces then enter the body and over a long period of time, sometimes twenty years or more, the insidious Chagas disease develops. Quite often patients do not know they have the disease. In around 30% of cases though, a chronic inflammatory response to the heart or digestive system can lead to death. The leishmaniases are transmitted by sandflies through the saliva whilst they feed on their victims. Depending on which species of the Leishmania parasite is transmitted, the disease can either occur in the skin (cutaneous leishmaniasis) or else migrate to the liver and spleen (visceral leishmaniasis). Some species, including Leishmania braziliensis, causes the horrible disease known in Brazil as Espundia, where human cells called macrophages (in which the parasite resides) migrate to the mucosal membranes of our lips and nostrils and cause them to disintegrate. Sometimes, following treatment, after a lapse that can last a few years, the visceral form of the disease relapses into a form we call post Kalar-Azar dermal leishmaniasis (PKDL).
Although drugs exist to treat both Chagas disease and the leishmaniases, they are far from ideal. Some are toxic, others have to be given over a protracted period, and several are available only by needle injections. Resistance has emerged to existing drugs, and it has been known for a long time that some parasites do not respond to treatment even if resistance has not been selected.
This collaborative project aims to bring together a team of researchers across the UK and Sao Paulo to look specifically at the processes that enable parasites to thrive in the insect vectors that carry them and then within the very different environment of their mammalian host. Since the parasites keep exactly the same genome (which is the blueprint that encodes every aspect of their ultimate makeup) they need to choose which parts of the genome to express in different environments. This involves subtle changes to the structure of the protein architecture that holds their genes together, in a structure we call chromatin. In other organisms it has, in recent years, become clear that the addition of small molecules to those chromatin-associated proteins can change their function. Removing those adaptations causes them to change back again. These alterations, which do not involve modifying the sequence of the DNA blueprint itself, and yet do influence how that DNA is expressed, are described as "epigenetic" alterations. We will investigate how epigenetic alterations impact on gene expression in T. cruzi and leishmanias, and work out how we can manipulate this epigenetic process by altering the availability of the small molecule metabolites responsible for those changes. We hope to find new therapeutic drugs treatment interventions to act on these epigenetic targets.
Although drugs exist to treat both Chagas disease and the leishmaniases, they are far from ideal. Some are toxic, others have to be given over a protracted period, and several are available only by needle injections. Resistance has emerged to existing drugs, and it has been known for a long time that some parasites do not respond to treatment even if resistance has not been selected.
This collaborative project aims to bring together a team of researchers across the UK and Sao Paulo to look specifically at the processes that enable parasites to thrive in the insect vectors that carry them and then within the very different environment of their mammalian host. Since the parasites keep exactly the same genome (which is the blueprint that encodes every aspect of their ultimate makeup) they need to choose which parts of the genome to express in different environments. This involves subtle changes to the structure of the protein architecture that holds their genes together, in a structure we call chromatin. In other organisms it has, in recent years, become clear that the addition of small molecules to those chromatin-associated proteins can change their function. Removing those adaptations causes them to change back again. These alterations, which do not involve modifying the sequence of the DNA blueprint itself, and yet do influence how that DNA is expressed, are described as "epigenetic" alterations. We will investigate how epigenetic alterations impact on gene expression in T. cruzi and leishmanias, and work out how we can manipulate this epigenetic process by altering the availability of the small molecule metabolites responsible for those changes. We hope to find new therapeutic drugs treatment interventions to act on these epigenetic targets.
Technical Summary
This programme of research will create a network of researchers studying the regulation of gene expression in the kinetoplastid protozoa, allowing us to dissect the processes that link metabolism, epigenetic change to chromatin, gene expression and cell differentiation. This will give insights into the processes that enable these organisms to enter a quiescent state that protects them from both immunological and chemotherapeutic intervention, and also provide novel targets against which to develop new drugs.
Specifically, we aim to characterise the range and extent of post-translational modifications to proteins (specifically histones) involved in chromatin formation in Trypanosoma cruzi and Leishmania infantum and L. mexicana cells undergoing passage through the life cycle and in response to metabolic pertubations. This will involve the isolation of chromatin from different parasite lifecycle stages, and isolation of the individual proteins of the complex (using immunopreciptation methodologies with antibodies specific for the trypanosomatid histones, and BioID approaches to identify neighbouring members of the complex). Proteomic approaches will determine the repertoire of proteins involved. Post-translational modifications (PTMs) on individual proteins will be assessed using specific antibodies and also mass spectrometry of digested proteins to seek mass changes consistent with different PTMs. The abundance of individual metabolites in cells at different cell/lifecycle stages will be determined using LC-MS based untargeted metabolomics. CRISPR/cas9 approaches will allow rapid knockout of non-essential enzymes producing metabolites implicated in PTM, and use of different metabolic substrates will also be used to modulate their abundance to asses impact on epigenetic change and gene transcription by RNAseq. Cell culture techniques will assess life cycle progression in mutants
Specifically, we aim to characterise the range and extent of post-translational modifications to proteins (specifically histones) involved in chromatin formation in Trypanosoma cruzi and Leishmania infantum and L. mexicana cells undergoing passage through the life cycle and in response to metabolic pertubations. This will involve the isolation of chromatin from different parasite lifecycle stages, and isolation of the individual proteins of the complex (using immunopreciptation methodologies with antibodies specific for the trypanosomatid histones, and BioID approaches to identify neighbouring members of the complex). Proteomic approaches will determine the repertoire of proteins involved. Post-translational modifications (PTMs) on individual proteins will be assessed using specific antibodies and also mass spectrometry of digested proteins to seek mass changes consistent with different PTMs. The abundance of individual metabolites in cells at different cell/lifecycle stages will be determined using LC-MS based untargeted metabolomics. CRISPR/cas9 approaches will allow rapid knockout of non-essential enzymes producing metabolites implicated in PTM, and use of different metabolic substrates will also be used to modulate their abundance to asses impact on epigenetic change and gene transcription by RNAseq. Cell culture techniques will assess life cycle progression in mutants
Planned Impact
The programme we propose will bring together a group of researchers from four UK institutions and the University of Sao Paulo in Brazil to investigate a crucial and yet hitherto relatively poorly studied aspect of the biology of protozoan parasites belonging to the order Kinetoplastida. Trypanosoma cruzi afflicts millions of people in Latin American causing Chagas disease, while the leishmaniases have a distribution spanning the world's tropical and sub-tropical regions. The groups that we are bringing together have expertise in many aspects of the biology of the causative parasites and covers parasite biochemistry, molecular and cell biology, metabolomics, proteomics and nucleotide sequencing. The group collectively brings together all of the skills required to learn about the epigenetic processes that allow the parasites to remodel their metabolic pathways to survive within the different environmental niches in which they find themselves. These can include the bloodstream and different intracellular environments in their mammalian hosts as well as different anatomical locations within the insect vectors that transmit them.
Epigenetic processes are those which enable profound changes in the physiology of an organism without requiring changes in the nucleotide sequence of their genomes. Generally, epigenetics involves remodelling of the structure of chromatin, which is the combined protein and nucleic acid structure that contains the genetic information. Chromatin remodelling can involve the post-translational modification of its protein components, for example histones. The modifications to chromatin-associated proteins are generally those of addition of small molecules, derived from cellular metabolism. As such, metabolism, and the accumulation or loss of particular metabolites, have a profound impact on how cells behave.
We will identify and characterise the post-translational modification in trypanosomes and leishmanias. We will then determine how these modifications influence gene expression as parasites move from one environment to another. As metabolism is ultimately responsible for providing the molecules that modulate chromatin, we will also probe the metabolism of these cells progressing through their life cycle.
Critically, it has recently become clear that T. cruzi and Leishmania parasites can enter a quiescent, non-proliferating state where they become tolerant of both immunological and chemotherapeutic assault. It is likely this process evolved (as in other microbes) to enable protection of the population against environmental fluctuations of many types (manifest in humans as immunological or drug intervention). As changes to genetic sequence are not associated with quiescence, epigenetics must be at play.
A key outcome of discovering the processes underpinning epigenetic influence on gene expression and phenotypic variation in these parasites will be to identify the process that drive quiescence. Since this process is responsible for long-term parasite persistence and drug treatment, this information will open the way to new strategies to prevent, or reverse, the formation of quiescent parasites, and thus create new avenues to assure successful treatment that will ultimately lead to control and elimination of Chagas disease and the leishmaniases, diseases which afflict tens of millions of people across the world today.
Epigenetic processes are those which enable profound changes in the physiology of an organism without requiring changes in the nucleotide sequence of their genomes. Generally, epigenetics involves remodelling of the structure of chromatin, which is the combined protein and nucleic acid structure that contains the genetic information. Chromatin remodelling can involve the post-translational modification of its protein components, for example histones. The modifications to chromatin-associated proteins are generally those of addition of small molecules, derived from cellular metabolism. As such, metabolism, and the accumulation or loss of particular metabolites, have a profound impact on how cells behave.
We will identify and characterise the post-translational modification in trypanosomes and leishmanias. We will then determine how these modifications influence gene expression as parasites move from one environment to another. As metabolism is ultimately responsible for providing the molecules that modulate chromatin, we will also probe the metabolism of these cells progressing through their life cycle.
Critically, it has recently become clear that T. cruzi and Leishmania parasites can enter a quiescent, non-proliferating state where they become tolerant of both immunological and chemotherapeutic assault. It is likely this process evolved (as in other microbes) to enable protection of the population against environmental fluctuations of many types (manifest in humans as immunological or drug intervention). As changes to genetic sequence are not associated with quiescence, epigenetics must be at play.
A key outcome of discovering the processes underpinning epigenetic influence on gene expression and phenotypic variation in these parasites will be to identify the process that drive quiescence. Since this process is responsible for long-term parasite persistence and drug treatment, this information will open the way to new strategies to prevent, or reverse, the formation of quiescent parasites, and thus create new avenues to assure successful treatment that will ultimately lead to control and elimination of Chagas disease and the leishmaniases, diseases which afflict tens of millions of people across the world today.
Organisations
- University of Glasgow (Lead Research Organisation)
- UNIVERSITY OF EDINBURGH (Collaboration)
- Universidade de São Paulo (Collaboration)
- Oregon Health and Science University (Collaboration)
- UNIVERSITY OF NOTTINGHAM (Collaboration)
- Bordeaux Segalen University (Collaboration)
- Novartis (Collaboration)
- Pasteur Institute, Paris (Collaboration)
Publications
Acosta H
(2019)
Proteomic analysis of glycosomes from Trypanosoma cruzi epimastigotes.
in Molecular and biochemical parasitology
Alpizar-Sosa EA
(2022)
Amphotericin B resistance in Leishmania mexicana: Alterations to sterol metabolism and oxidative stress response.
in PLoS neglected tropical diseases
Alpizar-Sosa EA
(2022)
Genome deletions to overcome the directed loss of gene function in Leishmania.
in Frontiers in cellular and infection microbiology
Barbosa RL
(2020)
Proteomic analysis of Trypanosoma cruzi spliceosome complex.
in Journal of proteomics
Barrett MP
(2019)
Protozoan persister-like cells and drug treatment failure.
in Nature reviews. Microbiology
Brooke DP
(2021)
Truncated S-MGBs: towards a parasite-specific and low aggregation chemotype.
in RSC medicinal chemistry
Cockram PE
(2020)
Halogenated tryptophan derivatives disrupt essential transamination mechanisms in bloodstream form Trypanosoma brucei.
in PLoS neglected tropical diseases
Cuevas-Hernández RI
(2021)
An aromatic imidazoline derived from chloroquinoline triggers cell cycle arrest and inhibits with high selectivity the Trypanosoma cruzi mammalian host-cells infection.
in PLoS neglected tropical diseases
Damianou A
(2020)
Essential roles for deubiquitination in Leishmania life cycle progression.
in PLoS pathogens
Description | We have demonstrated that Leishmania mexicana parasites respond to purine depleted medium by ceasing to proliferate and demonstrates profound changes to their metabolism associated with this state. We believe this gives insight into how new drugs can target dormant parasites believed to be critical in thwarting activity of current drugs. Given the fact that we (a) lost staff time to furlough during the covid19 lockdown (b) Had staff seconded to the Lighthouse lab (Covid19 testing centre) to assist the national effort against Covid19 (c) Had financial support cut from the grant due to its being ODA associated funding (d) were refused a non-costed extension in spite of the above hindrances (e) Many months of repeated experimentation revealed that histone preparation from Leishmania species is not readily achieved though adaptation of standard methods.applied to other kinetoplastid parasites (f) serendipitous discoveries in seeking modes of action of anti-kinetoplastid compounds We altered focus of our work. Success has been achieved in histone related work ialongside metabolic shifts impacting histone modification and vice versa n T. cruzi through our Brazilian partners. That work is reported separately through the FAPESP funding partners With an ultimate aim of seeking new drugs that may be active against kinetoplastid protozoa we turned our attention to two pathways associated with epigenetic gene regulation in these parasites. 1. Inhibition of Coenzyme A biosynthesis. We discovered two separate compounds with potent anti-leishmanial activity that inhibit the synthesis of coenzyme A, which is the primary donor of acetyl gous used in epigenetic modifications of histones. Our discovery was achieved using a non targeted metabolomics approach to determine modes of action of leishmanicidal drugs. Elevated levels of metabolites of the pantothenate pathway and a decrease in Coeznyme A, acetyl Coenzyme A and the metabolite of the TCA cycle pointed to inhibition of either pantetheine phosphate adenyl transferase, or dephosphocoenzyme A kinase. Other changes included a dramatic increase in lysophospholipids and loss of phospholipids, associated with reduced coenyme A as a donor of fatty acyls. An unexpected increase in the pentose phosphate pathway was noted too along with decrease in cellular ATP. Addition of coeznyme A to parasite culture medium was able to rescue parasites from the activity of the new compounds. We have thus identified coenzyme A synthesis as a validated drug target in Leishmania and are currently assessing numerous additional datasets pertaining to the drug mode of action as we move towards writing up the data for publication and seeking follow up funding for further development of these compounds. 2. Inhibition of methyltransferase activity by anti-kinetoplastid benzoxaboroles. Work carried out prior to this grant on trypanocidal benzoxaboroles had indicated that exposure of parasites to the drug leads to an accumulation of s-adenosylmethionine, which is the primary donor of methyl groups in cellular processes including epigenetic modification of DNA. Benzoxaboroles are now in clinical development against human African trypanosomiasis, and preclinical development against leishmaniasis and Chagas disease. Other work (carried out prior to this grant) indicated that development of resistance to benzoxaboroles in Trypanosoma brucei was associated with an alteration to transcriptional profiles of these parasites, such that their transcriptional profile as bloodstream forms in culture actually resembled procyclic forms. We, therefore, decided to determine whether benzoxaboroles of the valylester subclass (which are under preclinical development for Chagas disease and also animal African trypanosomiasis) might also trigger resistance in a similar way and in Glasgow, where we are not licensed to work with T. cruzi, used Trypanosoma congolense as a model to select resistance to a range of benzoxaborole compounds of the valylester class. Most yielded resistance through loss of serine peptidases involved in activation of these compounds by cleavage of the linker region, releasing a carboxylate derivative of the benzoxaborole warhead. One line, however, did not carry mutations to this gene, not amplification of the CPSF3 gene believed to encode one target of these compounds. Phenotypic analysis, genome and transcriptome sequencing have not yet identified the mechanism of resistance in this line. We have also initiated a new collaboration with Professor Gerald Spath in Paris to understand the metabolic effects of methyltransferase inhibitors designed to inhibit epigenetic processes in Leishmania infected macrophages (metabolomics data acquired, results under study). We have also conducted further collaborative work with Professor F Bringaud in Bordeaux who has developed a system whereby African trypanosomes alter their metabolism when grown in medium with glycerol rather than glucose as a main carbon source and we have conducted single cell RNA sequencing work and metabolomics analysis to determine the transcriptional and metabolic pathway alterations associated with the shift. In late 2022 we were awarded, through the University of Glasgow, some EPSRC originating funds to help complete our work. I was delighted to be able to appoint Dr Gould, one of the original post-docs on the MRC-Newton award who volunteered to join the national effort to combat the coronavirus pandemic. He was able to demonstrate that the compounds active against coenzyme A synthesis in Leishmania target dephosphoCoA kinase. Moreover, the same enzyme is not targeted by these compounds in African trypanosomes. A further discovery was made in that another class of compounds (the Strathclyde minor groove binders) appear to exert their mode of action binding to specific sites in trypanosome DNA indicative of a role for chromatin structure. Additional money became available through an EPSRC grant to the University of Glasgow. We were able to use that grant to continue our work on the coenzyme A synthesis pathway and have now expressed two Leishmania dephosphocoenzyme A kinase enzymes. We were also able to conclude a crucial piece of work on Topoisomerase II as a target for novel cyanotriazole based compounds developed by Novartis, with great potency against all trypanosomatids and now proceeding through a pre-clinical drug development pathway. |
Exploitation Route | We plan to seek whether histone changes are related to the phenotype and metabolic changes detected. The system we have developed offers a route to screen for compounds against dormant ("persister") type parasites and we believe this can be used by others in screening for new chemicals that will be active against such parasites. We have identified the coenzyme A synthetic pathway as a novel drug target in Leishmania. Others may seek new compounds to inhibit enzymes of this pathway (and a grant has been submitted with colleagues to take this further). The original submission was unsuccessful but a PhD student has now picked up on that work and once we have definitive evidence on the role of dephosphocoenzyme A kinase as a drug target in Leishmania we will re-submit. Our work with Novartis on cyanotriazole compounds that inhibit topoisomerase is progressing through a pre-clinical drug development. That partnership has also led to our repurposing some exceptional compounds as potential veterinary trypanocides. |
Sectors | Healthcare Pharmaceuticals and Medical Biotechnology |
URL | https://bv.fapesp.br/en/auxilios/103479/a-network-for-an-integrative-biology-in-neglected-diseases-bridging-epigenetics-metabolism-and-cell-/ |
Description | Drs Matthew Gould and Federica Giordani are employed by this grant. From May 2020 until September 18th for Dr Giordani and ongoing for Dr Gould, they took secondments to the Lighthouse lab in Glasgow where they joined the team producing high throughput testing of Covid19. Both became highly valued members of staff, leading teams in various aspects of the testing workflow. The laboratory has now performed over 10 million tests, has been instrumental in the national effort against Covid-19. Professor Barrett, the PI, was part of the team that established the Lighthouse laboratory too and lead research and training there until end of October 2020. He lead a training programme that up until that point had trained over 500 staff in the processes required to run the lab. Despite limitations arising from the COVID19 pandemic, we have been able to make significant progress with project aims. Work in Glasgow has focused on optimisation of methods to characterise post-translational modification of histones in Leishmania. We have maintained a fruitful exchange of knowledge between UK and Brazilian collaborators. Despite the secondment of research staff to COVID19 testing efforts, the involvement of Glasgow Polyomics, which has been working at approaching normal capacity apart from a 4 month hiatus (March 2020 - June 2020), has meant that we are able to collect detailed proteomic data from samples generated both in Glasgow and Sau Paulo. As a coda, we received an additional grant (part of a block grant to the University of Glasgow that was made available for proposals to pursue GCRF-Newton awards that had been operative across the pandemic. We were delighted to progress two drug development projects linked to our original plans through this "epigenetics and metabolism" grant. One, showing how a couple of anti-leishmanial compounds target the dephosphocoenzyme A biosynthetic pathway has reached a point where the data on dephosphocoenzyme A as a target are compelling. We were also able to gather the definitive evidence that a series of compounds developed by Novartis target topoisomerase IIalpha in trypanosomatids and these compounds are now being developed further by our partners. |
First Year Of Impact | 2023 |
Sector | Healthcare,Pharmaceuticals and Medical Biotechnology |
Impact Types | Societal |
Description | Food and Agriculture Organisation of the United Nations (FAO) - Advisory committee on rolling out a Progressive Control Pathway for Animal African trypanosomiasis |
Geographic Reach | Africa |
Policy Influence Type | Membership of a guideline committee |
Impact | Working towards a progressive control pathway for animal African trypanosomiasis (AAT) brings with it improvements to the welfare and health of livestock animals (primarily cattle) in Africa |
URL | http://www.fao.org/3/i7587e/i7587e.pdf |
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 | A distinct mode of DNA replication initiation in trypanosomes? |
Amount | £756,872 (GBP) |
Funding ID | BB/W001101/1 |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2022 |
End | 09/2025 |
Description | Identification and validation of a novel drug target in the Coenzyme A biosynthesis pathway in Leishmania |
Amount | £46,353 (GBP) |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 08/2022 |
End | 03/2023 |
Description | Precision Medicine PhD project |
Amount | £100,000 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 09/2020 |
End | 10/2023 |
Description | Wellcome Investigator Award |
Amount | £1,655,328 (GBP) |
Funding ID | 224501/Z/21/Z |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 06/2022 |
End | 07/2027 |
Title | Genome-scale metabolic models highlight stage-specific differences in essential metabolic pathways in Trypanosoma cruzi |
Description | Flux balance analysis model of T. cruzi metabolism |
Type Of Material | Computer model/algorithm |
Year Produced | 2020 |
Provided To Others? | Yes |
Impact | A model of T. cruzi metabolism, enabling identification of choke points to point to drug targets |
URL | https://pubmed.ncbi.nlm.nih.gov/33021977/ |
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 |
Title | single cell analysis of T. brucei long slender to short stumpy differentiation, and of cell cycle |
Description | RNA expression changes descibed at single cell level |
Type Of Material | Database/Collection of data |
Year Produced | 2021 |
Provided To Others? | Yes |
Impact | 2 papers to date |
Description | Collaboration with Novartis Institute of Tropical Diseases (Emeryville, CA, USA - note the archived address is out of date) |
Organisation | Novartis |
Department | Institute for Tropical Diseases Research |
Country | Singapore |
Sector | Private |
PI Contribution | We have screened Novartis compounds for activity against trypanosomes and leishmania, then sought drug modes of action for example, using untargeted metabolomics. We have verified drug targets e.g. topoisomerase II using CRISPR-cas9 editing of the gene to introduce mutations |
Collaborator Contribution | Novartis have generated a multitude of molecules and found many active against trypanosomatids. They have initiated mode of action studies and completed full ADME-tox analysis in order to select compounds for pre-clinical and later clinical development. |
Impact | Publications are listed. The project is interdisciplinary. Novartis produce chemicals, screen for activity, work on mode of action, pharmacology and all key aspects of drug development. We work on identifying drug modes of action and resistance. We are also testing compounds for activity against the trypanosome species that cause veterinary disease with a view to initiate development of new compounds for these diseases of great agricultural value. |
Start Year | 2016 |
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 - Oregon Health Science University |
Organisation | Oregon Health and Science University |
Country | United States |
Sector | Academic/University |
PI Contribution | We have tested the impact of these compounds on Leishmania metabolism and revealed them to target the Coenzyme A pathway, which we have confirmed by rescuing against drug action by addition of Coenzyme A exogenously. |
Collaborator Contribution | We received leishmanicidal compounds from Professor Scott Landfear which he had previously tested in vitro and in vivo and demonstrated potent anti-parasite activity. |
Impact | The compounds received from Professor Landfear were shown in our untargeted metabolomics platform to impact on Coenzyme A production with various knockon effects across the metabolome. Hence we have been conducting numerous experiments to confirm that it is either pantetheine phosphate adenhyltransferase, or dephosphoCoA kinase that is the target of these compounds, and have thus identified a novel mode of action for drugs against leishmania. This work will enable further drug development against these parasites. The work is interdisciplinary involving medicinal chemistry, anti-parasite drug screening and drug target deconvolution. |
Start Year | 2020 |
Description | Glasgow - Sao Paolo Collaboration |
Organisation | Universidade de São Paulo |
Country | Brazil |
Sector | Academic/University |
PI Contribution | Working to purify histones and other proteins involved in epigenetics in trypanosomatids and characterise post-translational modifications |
Collaborator Contribution | WE have worked on histone urification from Leishmania, the Brazilian group on Trypanosoma cruzi |
Impact | To date we are still in the methodological development stage. |
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 Pasteur |
Organisation | Pasteur Institute, Paris |
Country | France |
Sector | Charity/Non Profit |
PI Contribution | We have analysed the impact of a number of inhibitors of methyltransferases believed to impact epigenetic events in Leishmania parasites on their cellular metabolome |
Collaborator Contribution | Professor Spath's team have assessed activity of methyltransferase inhibitors on Leishmania development and sent compounds with anti-leishmanial activity to us for metabolomics testing, |
Impact | To date we have collected metabolomics data to assess impact of methyltransferase inhibitors designed to interfere with epigenetic processes on leishmania metabolism |
Start Year | 2021 |
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 | Conference - Epigenetics and the regulation of gene expression in kinetoplastid protozoa |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | This was an international conference directly related to this project where the project members were joined by over 100 other scientists with a strong postgraduate student representation |
Year(s) Of Engagement Activity | 2021 |
URL | https://mobile.twitter.com/Barrett_Lab/status/1395782382511398916 |
Description | Lecture on the Scottish Encounter with Tropical Disease to the University of the Third age in Helensburgh |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | I gave a lecture outlining the role of Scottish investigators in discovering the agents of tropical diseases and was able to link to the current status of tropical infectious diseases in the world today related to important Scottish research in a global context. |
Year(s) Of Engagement Activity | 2020 |
Description | Lecture to the Helensburgh University of the Third age on the Coronavirus pandemic |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | I gave an overview of the coronavirus pandemic to the University of the third age in Helensburgh |
Year(s) Of Engagement Activity | 2020 |
Description | Magazine article - About vaccination |
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 | THis article discussed the problems of vaccine scepticism |
Year(s) Of Engagement Activity | 2018 |
URL | https://www.newstatesman.com/politics/health/2018/05/how-fake-science-costing-lives-malign-rise-anti... |
Description | Magazine article about new variants of the SARS-Cov-2 coronavirus |
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 | The New Statesman is a UK based weekly political and current affiars magazine with 36,000 subscribers and over 200,000 online subscribers. It is read by most UK politicians. |
Year(s) Of Engagement Activity | 2021 |
URL | https://www.newstatesman.com/politics/health/2021/01/truth-about-new-covid-19-variants |
Description | Magazine article about the success of new interventions against neglected tropical diseases |
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 | THis magaaine article summarised the successes the 21st Century has had in developing new interventions against neglected tropical diseases |
Year(s) Of Engagement Activity | 2019 |
URL | https://www.newstatesman.com/world/africa/2019/08/how-world-winning-fight-against-neglected-tropical... |
Description | Magazine article discussing the discovery of antibiotics and ethics of drug testing |
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 in high standing UK current affairs weekly magazine, sparked further media interest afterwards and great interest from among the magazines 36,000 subscribers (>200,000 online subscribers) |
Year(s) Of Engagement Activity | 2020 |
URL | https://www.newstatesman.com/international/science-tech/2020/09/lesson-antibiotics-race-science-must... |
Description | Magazine article on coronavirus and human evolution |
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 | This article in the New statesamn discused viral and human genetic evolution in light of the competition between host and pathogen in the context of the covid-19 causing coronavirus |
Year(s) Of Engagement Activity | 2020 |
URL | https://www.newstatesman.com/science-tech/coronavirus/2020/03/what-makes-us-vulnerable-covid-19 |
Description | Magazine article on coronavirus immunity |
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 in high standing UK current affairs weekly magazine, sparked further media interest afterwards and great interest from among the magazines 36,000 subscribers (>200,000 online subscribers) |
Year(s) Of Engagement Activity | 2020 |
URL | https://www.newstatesman.com/science-tech/coronavirus/2020/04/can-you-catch-covid-19-twice |
Description | Magazine article on the 200th anniversary of the death of poet John Keats from tuberculosis and its link to Covid19 today |
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 | The New Statesman is a UK based weekly current affairs and political magazine. It has 36,000 subscribers and over 200,000 on line readers. It is read by most UK politicians. |
Year(s) Of Engagement Activity | 2021 |
URL | https://www.newstatesman.com/culture/books/2021/02/why-keats-s-haunting-reflections-tuberculosis-res... |
Description | Magazine article on the UK "Kent" coronavirus variant |
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 | The New Statesman is a leading UK based, but internationally read weekly current affairs magazine read by most UK politicians. It has a subscriber based of 36,000 plus online subscription based of >200,000 readers |
Year(s) Of Engagement Activity | 2020 |
URL | https://www.newstatesman.com/science-tech/coronavirus/2020/12/how-dangerous-new-covid-19-variant |
Description | Magazine article on the flawed concept of herd immunity for Covid19 |
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 in high standing UK current affairs weekly magazine, sparked further media interest afterwards and great interest from among the magazines 36,000 subscribers (>200,000 online subscribers) |
Year(s) Of Engagement Activity | 2020 |
URL | https://www.newstatesman.com/politics/health/2020/10/why-herd-immunity-not-option-uk-it-faces-covid-... |
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 | Public understanding of science lecture. The impact of Covid 19 on Neglected tropical diseases. St. Andrews Clinics for children (by Zoom) 25th Jan 2022 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Supporters |
Results and Impact | In this talk I discussed the impact of the coronavirus pandemic in Africa and how it influences efforts aginst other diseases there, e.g. neglected tropical diseases. Fruitful discussion was had with members of the public that support a charity that funds chilldrens hospitals in Africa |
Year(s) Of Engagement Activity | 2022 |
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 |
Description | The next pandemic |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | Talk to sixth formers at the High School of Glasgow on the risks of a new pandemic following the Covid19 crisis |
Year(s) Of Engagement Activity | 2022 |
Description | Times Radio interview on the meeting between Dr Livingstone and Henry Stanley in 10 Nov 1871 |
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 Times radio about the legacy of Dr Livingstone in medicine and exploration |
Year(s) Of Engagement Activity | 2020 |
URL | https://www.thetimes.co.uk/radio |
Description | Times radio interview on the 200th anniversary of the death of John Keats and his descriptions of tuberculosis (23 Feb 2021) |
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 about the impact of John Keats (poet) and how the tuberculosis from which he died influenced his work, and also explained how TB continues to affect the world today |
Year(s) Of Engagement Activity | 2021 |
URL | https://www.thetimes.co.uk/radio |
Description | Webinar - to New Statesman magazine readers |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | A webinar hosted by the New Statesman alongside Dr Phil Whitaker and Laura Spinney discussing the Covid19 pandemic |
Year(s) Of Engagement Activity | 2020 |
URL | https://www.newstatesman.com/2020/05/watch-new-statesman-webinar-pandemics-past-present-and-future |
Description | Webinar for business |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | I gave a series of five webinars in 2020 to Investec plc discussing the science behind the coronavirus pandemic |
Year(s) Of Engagement Activity | 2020 |
URL | https://www.investec.com/en_gb/focus/economy/economic-webinar-replay-professor-michael-barrett.html |
Description | Webinar. Covid 19. Investec 14th Dec 2021 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | Investors and employees of Investec joined a dsicussion about the Covid19 pandemic, seeking advice on how to respond to the virus both personally and in business practice. |
Year(s) Of Engagement Activity | 2021 |
Description | Webinar. Covid 19. Investec 30th Sept 2021 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | Webinar updating Investec and their investor community on Covid19 situation. Lots of Discussion about how individuals and businesses should respond. |
Year(s) Of Engagement Activity | 2021 |
Description | Webinar. Covid 19.Update Investec 14th Dec 2021 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | Webinar updating on the Covid19 pandemic |
Year(s) Of Engagement Activity | 2021 |
URL | https://www.investec.com/en_gb/focus/economy/economic-webinar-replay-variants-vs-vaccines.html |