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Final Report Summary - PARAMET (A systematic analysis of parasite metabolism - from metabolism to intervention)

ParaMet established a European multi-site training network of 12 Early Stage Researchers (ESRs) and 2 Experienced Researchers (ERs) across 11 host organisations, in the academic and industrial sectors. The ParaMet consortium was completed with Associated Partner Medivir. This four year Initial Training Network (ITN) was coordinated at the University of Glasgow by Professor Sylke Müller until September 2015 and subsequently by Professor Michael Barrett. The ParaMet project was made possible by grant funding from the European Commission’s Marie Curie Actions programme.

A public website for ParaMet was created and updated throughout the project to reflect the latest events and publications. Full details of our partners and their contact information can be found on the ParaMet website: http://www.paramet.eu/

The core focus of the ParaMet programme was the investigation of parasitic protozoa that pose a major threat to human and animal health and exact devastating social and economic costs across the globe. We primarily focused on the causative agents of malaria (Plasmodium), sleeping sickness (Trypanosoma) and leishmaniasis (Leishmania) that have an enormous effect in tropical areas, but some parts of Europe are also endemic for leishmaniasis and tens of thousands of imported malaria cases are reported in Europe annually. In addition, the protozoan parasite Eimeria causing major disease in chickens and impacting significantly on food production within Europe and worldwide, was subject of the investigations. Treatments currently available against these parasites are limited by severe side-effects, development of drug resistance, and/or high cost and inadequate means of administration. Therefore the main objectives of this programme were:
• To employ novel omics techniques to identify and validate new drug targets in the parasites
• To use advanced phenotypic and structural approaches to empirically and rationally identify new chemical compounds that inhibit parasite growth.

European research has always been at the forefront of the battle against diseases caused by parasitic protozoa and ParaMet has brought together exceptional expertise from European science and the pharmaceutical industry offering state-of-the-art training to ESRs and ERs in methods required for drug development focusing on parasitic protozoa. Our aims were to establish a platform that merges the expertise of academic scientists from leading centres of excellence in key areas of parasitology research with experts from industrial partners that will help to integrate and translate the biological findings into future intervention strategies.

ParaMet was divided into 4 separate research work packages focusing on different levels of the drug development process. 12 ESRs and 2 ERs were recruited to the programme to carry out the associated research projects. The ERs were located with the industrial partners and were involved in setting up new platforms for phenotypic screening of chemical entities and to use medicinal chemistry approaches to specifically screen new chemicals against specific protein targets. The ESRs were involved in scientific research projects in academic laboratories that over the period of their employments led to the discoveries that parasite metabolic functions are highly adaptable and respond to environmental changes in unusual and unexpected ways. The approaches used were the generation of gene deletion mutants of the parasites and assessing their phenotypes by transcriptomics, proteomics and metabolomics. The data emphasise that the metabolism of protozoan parasites is extremely adaptable and that they can survive unfavourable conditions and this provides new insights into the metabolic flexibilities that need to be taken into consideration when deciding on the suitability of a future drug target.

We also employed cutting edge forward genetics approaches (RNAi screens; whole genome over-expression) and identified targets of drugs and inhibitors and pinpointed processes in the parasites that are crucial for their survival. These technologies provide new platforms for future drug screening efforts and have generated useful and exciting information that our industrial partners will take forward for their drug discovery projects.

Phenotypic screening approaches identified new drug candidates against Leishmania, Trypanosoma and Plasmodium and new chemical scaffolds were established through natural product screening against these parasites. On the other hand rational approaches determining the structure of specific proteins and using compound library screens against these proved very successful with several protein structures solved during the duration of the programme enabling targeted compound screens based upon this structural information. Medicinal chemists are now working on the improvement of existing lead compounds and will provide their expertise to improve chemical entities that are being identified through the screening methods as potential chemotherapeutic leads.

The regulation of gene expression was investigated in Plasmodium with particular emphasis on epigenetic control mechanisms and new and possibly parasite-specific ways controlling heterochromatin formation were identified that may be exploitable for future drug development. These discoveries will be essential stepping stones towards a clearer comprehension of the interplay between metabolism and epigenetic regulation.

This extended knowledge as well as the extensive “omics” datasets that were generated throughout the programme were provided to mathematicians who improved and generated metabolic models that identify possible vulnerabilities in the system “parasite” that are exploitable for drug discovery efforts. Emerging from these new, publically available databases, such as trypanocyc (http://vm-trypanocyc.toulouse.inra.fr/), will also enable others to exploit the information gained.

In relation to training; throughout the ParaMet project fellows benefited from 7 varied and extensive training courses; in Glasgow (M10, M18 and M22), Crete (M25), Madrid (M28), Toulouse (M34), and Heidelberg (M37). The training courses covered a wide range of scientific areas and offered the fellows opportunities to extend their understanding and approaching scientific problems and to engage in lateral thinking. In addition, fellows were trained in complementary skills ranging from extensive communication and presentation skills improving the quality and effectiveness of interacting and communicating with others and transferring their scientific knowledge and experience to both a scientific and non-scientific audience. This was effectively exploited in the design of the ParaMet webpage and their multiple and enthusiastic engagements with the public through outreach activities; in addition, their intense and frequent attendance and presentation at scientific meetings helped them to perfect these skills. The fellows also attended an enterprise and entrepreneurship workshop providing them with an understanding of how to translate scientific discoveries into commercial outputs. In summary, ParaMet fellows have received diverse and challenging training opportunities and our training programme has received excellent feedback. ParaMet’s multidisciplinary and highly collaborative training programme has already proven extremely valuable as a great number of fellows have already secured positions in the academic or non-academic sector to pursue their careers. This is clearly due to the confidence and excellence that these young scientists have acquired during their training. We believe that ParaMet was an extremely successful training programme that has trained and educated ERs and ESRs into young scientists of the future.

Overall ParaMet integrated advanced and specialised methodologies to identify and validate druggable targets in protozoan parasites threatening human and animal health. We are confident that parts of this research will now move rapidly into industry-based drug discovery programmes and thus have direct impact on the improvement of health and economy not least by having re-engaged some of the industrial partners with the development of antiparasitic drugs for human and animal diseases. In addition, ParaMet has trained a cohort of enthusiastic and excellent young scientists to doctorate level that are keen to continue a career in academic or non-academic science, particular focusing on efforts to improve human and animal health in Europe and world-wide. This was an extremely successful network that has not only led to the successful education of new promising scientists but also has led to the generation of numerous new collaborations of the Principal Investigators (PIs) which will be highly beneficial for the future of European science.

Related information

Contact

Michael BARRETT, (Professor of Biochemical Parasitology)
Tel.: +44 141 330 6904
E-mail
Record Number: 192607 / Last updated on: 2016-12-14
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