INDIVIDUAL PROJECTS (ESR positions) in the MepAnti ITN

ESR 1: Biophysical and structural characterisation of DXS, DXR and IspD (in complex with inhibitors)

Research group of Prof. Matthew Groves, University of Groningen – Groningen Research Institute of Pharmacy, Dept. of Drug Design.

Position in Structural Biology in Drug Design

Link of the group: http://structuralbiologyindrugdesign.wordpress.com and https://www.rug.nl/staff/m.r.groves/

Required skills:
The ESR must hold a Master’s degree in biology/biochemistry/physics/chemistry or mathematics. (S)he must have an interest in biochemistry, biophysics & infectious diseases. A basic knowledge of medicinal chemistry and/or fragment screening would be considered an advantage

Project description:
This project will focus on the structural analysis of DXS and IspD enzymes form a variety of pathogenic organisms (including malaria and tuberculosis) to support the design and synthesis of selective and potent inhibitor(s) of the MEP pathway. As initial crystallisation conditions for the tubercular enzyme are available, the initial stages will focus on a fragment screen of this system, but the successful candidate would be expected to apply these successful approaches to the DXS of other organisms of interest. The ESR will need to be able to liaise closely with the other ESRs to provide structural data to drive compound evolution. Training in cutting edge X-ray data collection and biophysical techniques will be provided.

ESR 2: Biophysical and structural characterisation of IspE and IspF (in complex with inhibitors)

Research group of Prof. Wulf Blankenfeldt, Helmholtz Centre for Infection Research (HZI) Braunschweig.

Position in Structural biology

Link of the group: https://www.helmholtz-hzi.de/en/research/research-topics/bacterial-and-viral-pathogens/structure-and-function-of-proteins/wulf-blankenfeldt/

Required skills:
The ESR must hold a Master’s degree in chemistry, physics or biochemistry with basic knowledge of crystallography, interest in biomolecular structure and ligand interactions.

Project description:
This component of the project will focus on the characterization of structures of the enzymes of the MEP pathway namely IspE and IspF, with inhibitors together with biophysical characterization of ligand interactions (kinetic and thermodynamic aspects). The project will extend from production and use of recombinant protein production systems, purification and crystallization, structure determination, use of ITC and SPR to study ligand binding.

ESR 3: Biophysical and structural characterisation of IspG and IspH (in complex with inhibitors)

Research group of Dr. Franck Borel, Commissariat à l’énergie atomique et aux énergies alternatives (CEA), Synchrotron Group, Institut de Biologie Structurale, Grenoble.

Position in Structural-biology

Link of the group: https://www.ibs.fr/research/research-groups/synchrotron-group/

Required skills:
The ESR must hold a Master’s degree in biochemistry, biophysics or related fields. Skills in biochemistry are required. Although training will be provided, additional knowledge and first hands-on experience in crystallography would be considered a strong advantage. Knowledge of French language is not required but can help in daily life. The successful candidate will be enrolled at the University of Grenoble Alpes.

Project description:
The project is centered on the structural analysis of IspG and IspH, in a drug design approach. The approach involves biochemistry, crystallography and in silico docking and design.

ESR 4: Design and synthesis of inhibitors of the enzymes DXS and IspD

Research group of Prof. Anna K. H. Hirsch, Helmholtz-Zentrum für Infektionsforschung GmbH (HZI) – Helmholtz Institut für Pharmazeutische Forschung Saarland (HIPS)

Position in Medicinal Chemistry

Link of the group: www.helmholtz-hzi.de/hirsch

Required skills:
The ESR must hold a Master’s degree in synthetic organic chemistry. A (basic) knowledge of medicinal chemistry and an interest in biochemistry or microbiology would be considered an advantage.

Project description:
This project will focus on the design and synthesis of selective and potent inhibitor(s) of the DXS and IspD enzymes of the MEP pathway. The ESR will embrace two perspectives: optimisation of already identified promising compounds with antiparasitic activity and the optimisation and/or fragment growing of novel and unreported chemical structures. The pool of compounds will span from fragments to natural products and according to the in vitro and in cellulo activities, the most promising scaffolds will be further optimised. The possibility to use also innovative hit-identification strategies (such as dynamic combinatorial chemistry and target-guided synthesis) will enhance the successful identification of good starting points. The successful candidate will be enrolled at Saarland University and the local graduate school.

ESR 5: Synthesis of prodrugs of DXR inhibitors

Research group of Prof. Serge Van Calenbergh, Ghent University, Faculty of Pharmaceutical Sciences Laboratory for Medicinal Chemistry.

Position in Medicinal Chemistry

Link of the group: www.medchem.ugent.be

Required skills:
The ESR must hold a Master’s degree in synthetic organic chemistry, basic knowledge of medicinal chemistry, interest in biochemistry/microbiology.

Project description:
This project will mainly focus on the design and synthesis of selective and potent new inhibitor(s) of DXR, as well as prodrugs of existing phosphonate-based DXR inhibitors. Prodrug strategies will be explored to

    • improve the poor pharmacokinetic properties of existing phosphonate lead compounds.
    • expand the activity profile of fosmidomycin analogues to other microorganisms

The underlying rationale is the observation that fosmidomycin and multiple analogues of this natural phosphonate product demonstrate promising antiplasmodial activitiy, but fail to show promising antibacterial activity even when the inhibitory activity for bacterial and plasmodial DXR is comparable. This discrepancy is due to the fact that P. falciparum infected erythrocytes use parasite-induced permeability pathways for the uptake of fosmidomycin in infected red blood cells, while such transport mechanisms are absent in bacteria.

ESR 6: Design and synthesis of inhibitors of the enzymes IspE and IspF

Specs Research Laboratory

Position in Organic Chemistry

Link of the group: https://www.specs.net/

Required skills:
ESR must hold a Master’s degree in synthetic organic chemistry, basic knowledge of medicinal chemistry, interest in biochemistry/microbiology and cheminformatics.

Project description:
This project will focus on the design and synthesis of selective and potent inhibitor(s) of the IspE and IspF enzymes of the MEP pathway. The project will embrace two perspectives: optimization of already identified promising compounds with antiparasitic activity and the optimization and/or fragment growing of novel and unreported chemical structures. Optimisation will take into account biological data, SAR and structural data, undesired features, as well as physicochemical parameters such as aqueous solubility, LogP, logD. Furthermore, freedom to operate is taken into account which is essential for the development of new therapeutics.

ESR 7: Catalytic mechanism and inhibition of IspG and IspH

Research group of Prof. Myriam Seemann, Université de Strasbourg

Position in Medicinal Chemistry

Link of the group: http://institut-chimie.unistra.fr/en/research-groups/cbat-chimie-biologique-et-applications-therapeutiques/

Required skills:
The ESR must hold a Master’s degree in organic chemistry, medicinal chemistry, bioinorganic chemistry, biochemistry or related disciplines. The candidate should be willing to work at the interface of chemistry, biochemistry and biophysics. Due to the interdisciplinary nature of the project, demonstrated knowledge in synthetic chemistry and enzymology would be advantageous. Experience in protein expression and drug design will also be valued. The successful candidate will be enrolled in the Graduate School of Chemistry of the University of Strasbourg.

Project description:
This project will focus on the design and synthesis of inhibitors based on the breakthrough made in the elucidation of the mechanisms and on the resolution of the structures. The ESR will (i) participate in the design and synthesis of inhibitors (ii) express, purify but also characterise the enzymes using a combination of biophysical approaches (UV, RPE, crystallography…) (iii) evaluate the inhibition potential of the synthesised molecules (iv) validate the mode of action of the inhibitors (v) participate in the structure-based optimisation of the hits. The CBAT team will provide its expertise in organic synthesis as well as in the production, characterisation and enzymology of [4Fe-4S] enzymes. The laboratory is fully equipped with state-of-the-art gloveboxes to work under anaerobic conditions.

ESR 8: Fragment screening by BLI for inhibitors of the MEP pathway

Research group of Prof. Ruth Brenk, Department of Biomedicine, University of Bergen, Norway

Position in Biochemistry, biophysics

Link of the group: https://www.uib.no/en/rg/brenk

Required skills:
The ESR must hold a Master’s degree in biochemistry, biophysics, pharmacy or a related discipline, basic knowledge of protein chemistry, interest in medicinal chemistry/microbiology.

Project description:
The project will focus on hit discovery for the first five enzymes of the MEP pathway. The chemical space of these enzymes is currently underexplored. Therefore, we will conduct virtual and fragment screening with the goal to discover new inhibitors for these targets. A particular focus will be laid on hit validation to avoid wasting time with false positive hits. In collaboration with other fellows, the PhD student will also design derivates for the hits to improve their affinities.
Please take a close look to Qualifications and personal qualities for this ESR.

ESR 9: Fragment screening by NMR spectroscopy and cell-based testing of inhibitors of the MEP pathway

Research group of Prof. Anna K. H. Hirsch, Department of Drug Design and Optimization, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) – Helmholtz Centre for Infection Research (HZI).

Position in Biophysics and microbiology

Link of the group: www.helmholtz-hzi.de/hirsch

Required skills:
The ESR must hold a Master’s degree in organic chemistry with a focus on NMR spectroscopy. An interest or even some hands-on experience in microbiology or biochemistry would be considered an advantage.

Project description:
Fragment-based drug design is an established and successful technique used in drug discovery to identify novel hits. This project will make use of two large and chemically diverse libraries that will be screened using NMR-spectroscopy (STD-NMR and water LOGSY) against the first five enzymes of the MEP pathway. The potency of the most promising compounds will be confirmed and complemented by further biophysical techniques and by the determination of their enzyme inhibitory activity. Determination of the frequency of resistance development followed by sequencing of the genomes of resistant mutants will enable the validation of the intracellular target of selected inhibitors. The successful candidate will be enrolled at Saarland University and the local graduate school.

ESR 10: Characterisation of MEP pathway inhibitors in M. tuberculosis as antituberculotics

Research group of Prof. Norbert Reiling, Universität zu Lübeck (FZB)

Position in Parasitology / Drug Discovery

Link of the group: https://fz-borstel.de/index.php/en/sitemap/priority-research-area-infections-prof-dr-ulrich-schaible/microbial-interface-biology-pd-dr-norbert-reiling

Required skills:
The ESR must hold a Master’s degree in molecular biology, microbiology, biochemistry, infection biology or related fields. Strong skills in genetic manipulation of mycobacteria is beneficial. Experience working under biosafety level 3 (BSL3) conditions, e.g. with M. tuberculosis is highly welcome. Excellent communications skills and a strong interest in developing teaching materials for the public are desirable. The working language of the group is English and German. Knowledge of the German language will be appreciated.

Project description:
The main objective of this project is to evaluate the antimycobacterial activity of inhibitors of enzymes of the MEP pathway using drug-sensitive and drug-resistant M. tuberculosis bacteria in different systems. The ESR will screen identified actives for cytotoxic effects and evaluate actives with low cytotoxic activity in M. tuberculosis-infected macrophages. Screening will be followed by comparison of the antibacterial activity of selected compounds against conditional knockdown mutants of the target genes and the wildtype strain. Characterisation of the replication of the mutants in vitro and in primary human macrophages will elucidate the functional role of the target genes for M. tuberculosis replication. Finally, the successful candidate will evaluate MEP pathway inhibitors for combination chemotherapy.

ESR 11: Characterisation of MEP pathway inhibitors in Plasmodium falciparum as antimalarials

Parasite Chemotherapy Unit, Prof. Pascal Mäser, Swiss Tropical and Public Health Institute, Department of Medical Parasitology and Infection Biology, 4051 Basel, Switzerland

Position in Parasitology / Drug Discovery

Link of the group: https://www.swisstph.ch/en/about/mpi/parasite-chemotherapy/

Required skills:
ESR must hold a Master’s degree in the Life Sciences, skills in cell biology, basic knowledge of infection biology, interest in drug discovery.

Project description:
This project aims to identify inhibitors of the MEP pathway as new antimalarial leads. The synthesized inhibitors will be tested for their efficacy against drug-sensitive and drug-resistant strains of Plasmodium falciparum and their toxicity to mammalian cells. Active and selective molecules will be profiled regarding stage-specificity of action, speed of action, and further pharmacodynamic parameters. Drug combinations will be evaluated and the potential for transmission blocking. Drug resistant P. falciparum mutants will be selected for and characterized. Thus the project will provide the essentials in parasite biology and antimalarial drug action to the MepAntI network.

ESR 12: Chemical proteomics characterisation of MEP pathway inhibitors

OmicScouts GmbH – Proteomics for drug and biomarker discovery

Position in Proteomics and Chemical Biology

Link of the group: https://www.omicscouts.com/en/

Required skills:
The ESR must hold a Master’s degree in Biochemistry, Biotechnology, Analytical Chemistry, Biology or related field; required is prior knowledge of basic biochemical and cell biology methodology with a focus on protein analysis. Further, knowledge of and hands-on experience with mass spectrometry-based proteomics and chemical biology is highly desired. A high affinity to the analysis of large datasets by means of bioinformatics techniques will be taken into account as an asset.

Project description:
This project will focus on the elucidation and thorough analysis of individual MEP pathway enzyme inhibitor candidates by means of chemical biology and chemical proteomics. More specifically, biorthogonal chemistry, affinity pulldowns and photo-affinity labelling with subsequent tandem mass spectrometry as read-out technique will be called into action to reach this goal. Moreover, the project will investigate potentially evolving bacterial resistance mechanisms by genomics and proteomics. The test systems start from well-established tox cell culture models and will reach eventually the investigation in relevant pathogens to evaluate the true potential for the intended indication from an early stage.