Exploiting the methylerythritol phosphate pathway as a source of drug targets for novel anti-infectives.
Project description
Anti-infective resistance is a serious global healthcare issue, calling for the development of compounds with a novel mode of action. An interdisciplinary approach will afford potent and selective inhibitors of the underexplored methylerythritol phosphate pathway, a rich source of targets that are essential for medically relevant pathogens such as the causative agents of malaria and tuberculosis. The discovery of anti-infective agents requires a highly interdisciplinary approach. A lack of a coherent training on the fundamental aspects and design principles encompassing all relevant disciplines delays the discovery and optimisation of urgently needed candidates for commercial development.
This network aims to train the next generation of scientists with cutting-edge interdisciplinary skills in the discovery of new anti-infective agents through a an innovative training programme, setting the stage for the discovery of urgently needed anti-infectives with an unprecedented mechanism of action, as a springboard for translational research and industrial applications.
There is a natural progression in both the training and research programme from (i) structural biology of the target enzymes, via (ii) the design and synthesis of inhibitors to (iii) fragment screening as well as multiparameter optimisation including cell-based testing and profiling with chemical proteomics. This network unites leading experts with complementary expertise in anti-infective agents from across Europe and comprises 17 partners in total: 11 academic partners and 6 non-academic partners from 8 countries, including 3 SMEs (1 designing screening libraries, 1 using chemical proteomics for target identification/deconvolution and the study of resistance formation and 1 developing bioinformatics tools for drug discovery), 1 large pharmaceutical company and 2 charities focussing on neglected diseases and promoting science to the general audience.
Objectives
These are the objectives of MepAnti:
Elucidation of crystal structures of constituent enzymes from pathogenic organisms and their exploitation for the design of potent and selective inhibitors as anti-infective agents
Exploitation of various hit-identification strategies (rational design, synthesis, multiparameter optimization)
Fragment-based screening
Role of Ghent University
Fosmidomycin is a small, polar molecule that is a potent inhibitor of DXR but is devoid of significant antibacterial activity. To tackle this problem, we aim to develop prodrugs by converting fosmidomycin (analogues) into hydrophobic phosphonate prodrugs. This is expected not only to improve uptake in bacteria (by passive diffusion) but also oral bioavailability (another bottleneck in the use of fosmidomycin). After conversion into the parent drug in bacterial cells, pathogen growth will be arrested by inhibition of DXR by analogy to very successful antiviral drugs.
We will synthesise a range of fosmidomycin prodrugs and chemical probes for ESR12 and test these against relevant pathogens. We will avoid side effects or toxicity of the prodrug moiety after release of the parent drug. Furthermore, the ESR will also be involved in the optimization of selected fragment hits identified for other enzymes involved in the MEP pathway.
