Universidad San Pablo CEU and University of Glasgow

Start : July 2014 | Status : Complete

The scientist: Dr Emily Grace Armitage will focus her research on the discovery of new drugs for Leishmania donovani disease, through a project titled "Use of metabolomics to determine modes of action of novel anti-leishmanial compounds”. Emily is Postdoctoral Researcher at the Center of Excellence of Metabolomics and Bioanalysis (CEMBIO) in the Universidad San Pablo CEU with Prof. Coral Barbas, and has extensive experience in the metabolomic field where she has numerous publications of scientific relevance.

The sponsors: Universidad San Pablo – CEU (USP-CEU) and the University of Glasgow (UoG) house state of the art metabolomics platforms and have pioneered studies into the metabolomics of parasitic protozoa.  The combination of metabolomic platforms offered at USP-CEU provides complementary information covering a large proportion of the metabolome.  UoG houses the Scottish Metabolomics facility and has established a platform based on Fourier transform mass spectrometry coupled to liquid chromatography (as well as Gas chromatography–mass spectrometry, GC-MS, and Nuclear magnetic resonance, NMR). Bringing together these two centres offers an exciting opportunity to accelerate the implementation of metabolomics as a routine part of the drug target evaluation pathway. The UoG centre has pioneered studies demonstrating that metabolomics can identify targets of anti-protozoal drugs. USP-CEU have already demonstrated how their platform can identify changes in leishmania with resistance to antimonials and the mechanism of action of miltefosine in both wild and resistant parasites

Foundation funding: The Foundation is providing £ 150 K in support.

GSK’s contribution: GSK is providing in-kind contributions, including scientific expertise in leishmania to obtain the extracts from in vitro parasite culture, and access to Biosafety Level 3 facilities and to GSK´s collection of compounds.

Project Description: Screening of compound libraries for potential new antimicrobial agents has demonstrated the superiority of whole organism (phenotypic) screening to identify hits for further development.  Such screens require compounds to already demonstrate key pharmacological criteria required for parasite killing, including an ability to enter cells and find targets in situ.  However, phenotypic screens are hampered by the fact that drug targets are not known. This can hinder our ability to progress from hit to lead to drug, where target knowledge can guide medicinal chemistry in improving efficacy.
In recent years metabolomics has been applied to drug target discovery and also to identify resistance mechanisms.  This project aims to use metabolomics to identify modes of action of new compounds identified by phenotypic screening against Leishmania. Hits from the GSK anti-Leishmania screening campaign will be analysed firstly to allow clustering of drugs according to how they alter the metabolome and then focusing on a limited set of representatives to identify individual drug targets.  The proposed duration of the project is 18 months and will involve a close collaboration between the Universidad San Pablo CEU, the University of Glasgow and GSK’s Medicines Development Campus at Tres Cantos.