Chimie Biologique et Applications Thérapeutiques | CBAT

Le Bel Institute, 4th floor North

Geneviève STOLL
email : genstoll[at]unistra.fr
Phone : +33 (0)3 68 85 13 64

The research activities of the CBAT team are focused on the study of proteins with therapeutic potential, particularly in the field of antibacterials. Most of our projects aim at fighting bacteria for which current treatments are scares or ineffective. Antibiotic resistance is, in fact, a very serious health threat as some infections are already impossible to threat with the existing therapeutic repertoire.

The CBAT team offers the possibility of doing internships (Bachelor, Master, engineering schools students …) and to prepare a PhD thesis at the University of Strasbourg. The team provides a training through research at the interface of chemistry and biology giving the opportunity to gain a multidisciplinary mindset and skill set. Postdoctorates, doctorates, trainees may visit the laboratories of our collaborators notably within the framework of crystallography experiments at the European Synchrotron Radiation Facility (ERSF, Grenoble).

The research performed in the CBAT team requires a multidisciplinary approach combining bioorganic and bioinorganic chemistry, enzymology, microbiology, molecular biology, crystallography and spectroscopies. The team has all the expertise to produce and characterize oxygen-sensitive metalloenzymes.

• Investigation of the catalytic mechanism of enzymes and metalloenzymes (synthesis of molecular tools, SAR studies, site-directed mutagenesis…)
• Enzyme and metalloenzyme inhibition (synthesis of inhibitors, determination of inhibition constants and inhibition mode, structure determination of enzyme-inhibitor complex…)
• Characterization of Fe/S enzymes (EPR and Mössbauer spectroscopies…)
• Identification of biological partners involved in the reduction of metalloenzymes
• Characterization of protein assembly involved in electron transfer
• Identification of new targets for the development of novel antibacterial agents
• Drug discovery: Mechanistic-based, structure-based, fragment-based drug design, virtual screening, HTS…)
• Inhibition tests on enzymes and bacteria

• Interdisciplinary Thematic Institute InnoVec (https://iti-innovec.unistra.fr/) that tackles vectorization issues.

• JPI-AMR-VRI network: International Research Alliance for Antibiotic Discovery and Development (IRAADD, https://www.jpiamr.eu/iraadd/; https://www.iraadd.eu/)
  
  
• Marie Sklodowska Curie (ITN)-MepAnti (http://mepanti.hips-wordpress.helmholtz-hzi.de/), that aims at fighting antimicrobial resistance.

• Glove-box under anaerobic conditions dedicated to the purification of oxygen sensitive enzymes
• Protein purification systems
• Equipment for organic chemistry

V. Herrscher,C. Witjaksono,M. Buchotte,C. Ferret,F. Massicot,J.-L. Vasse,F. Borel,J.-B. Behr, M. Seemann
Irreversible inhibition of IspG, a target for the development of new antimicrobials, by a 2-vinyl analogue of its MEcPP substrate
Chem. Eur. J.2022, 28, e202200241. https://doi.org/10.1002/chem.202200241

 H. Jobelius, G. I. Bianchino, F. Borel, P. Chaignon, M. Seemann
The Reductive Dehydroxylation Catalyzed by IspH, a Source of Inspiration for the Development of Novel Anti-Infectives
Molecules, 27, 708 (2022). https://doi.org/10.3390/molecules27030708

M. Mauger, C.Ferreri, C. Chatgilialoglu, M. Seemann
The bacterial protective armor against stress: The cis-trans isomerase of unsaturated fatty acids, a cytochrome-c type enzyme.
J. Inorg. Biochem. 224: 111564 (2021): https://doi.org/10.1016/j.jinorgbio.2021.111564

M. Miethke, M. Pieroni, T. Weber, M. Brönstrup, P. Hammann, L. Halby, P. Arimondo, P. Glaser, B. Aigle, H. Bode, R. Moreira, Y. Li, A. Luzhetskyy, M. Medema, J.-L. Pernodet, M. Stadler, J. Tormo, O. Genilloud, A. Truman, K. Weissman, E. Takano, S. Sabatini, E. Stegmann, H. Brötz-Oesterhelt, W. Wohlleben, M. Seemann, M. Empting, A. Hirsch, B. Loretz, C.-M. Lehr, A. Titz, J. Herrmann, T. Jaeger, S. Alt, T. Hesterkamp, M. Winterhalter, A. Schiefer, K. Pfarr, A. Hoerauf, H. Graz, M. Graz, M. Lindvall, S. Ramurthy, A. Karlén, M. van Dongen, H. Petković, A. Keller, F. Peyrane, S. Donadio, L. Fraisse, L. Piddock, I. Gilbert, H. Moser, and R. Müller
Towards the sustainable discovery and development of new antibiotics
Nature Rev. Chem. 5, 726-749 (2021): https://www.nature.com/articles/s41570-021-00313-1

P. Chaignon, B. E. Petit, B. Vincent, L. Allouche, M. Seemann
Methylerythritol Phosphate Pathway: Enzymatic Evidence for a Rotation in the LytB/IspH-Catalyzed Reaction.
Chem. Eur. J.,2020, 26, 1032-1036. DOI:https://doi.org/10.1002/chem.201904676

Zoljargal Baatarkhuu, Philippe Chaignon, Franck Borel, Jean-Luc Ferrer, Alain Wagner, Myriam Seemann
Synthesis and Kinetic evaluation of an azido analogue of methylerythritol phosphate: a Novel Inhibitor of E.coliYgbP/IspD
Scientific REPORTS | (2018) 8:17892 | DOI:10.1038/s41598-018-35586-y

F. Borel, E. Barbier, S. Krasutsky, K. Janthawornpong, P. Chaignon, C. Dale Poulter, J.-L. Ferrer, M. Seemann
Further insight into crystal structures of E. coli IspH/LytB in complex with two potent inhibitors of the MEP pathway: a starting point for rational design of new antimicrobials.
ChemBioChem2017, 18, 2137-2144

Faus, A. Reinhard, S. Rackwitz, J. A. Wolny, K. Schlage, H.-C. Wille, A. Chumakov, S. Krasutsky, P. Chaignon, C. D. Poulter, M. Seemann, V. Schünemann
Isoprenoid biosynthesis in pathogenic bacteria: Nuclear Resonance Vibrational Spectroscopy provides insight into the unusual [4Fe-4S] cluster of the E. coli LytB/IspH protein.
Angew. Chem. Int. Ed.2015, 54, 12584-12587

L. Y. So, W.-Y.Chen, D. C. Lacap-Bugler, M. Seemann, R. M. Watt
pZMO7-Derived shuttle vectors for heterologous protein expression and proteomic applications in the ethanol-producing bacterium Zymomonas mobilis.
BMC Microbiology2014, 14, 68-84

K. Janthawornpong, S. Krasutsky, P. Chaignon, M. Rohmer, C.D. Poulter, M. Seemann 
Inhibition of IspH, a [4Fe-4S]²⁺ enzyme involved in the biosynthesis of isoprenoids via the MEP pathway.
J. Am. Chem. Soc.2013, 135, 1816-1822

A. Ahrens-Botzong, K. Janthawornpong, J. A. Wolny, E. Ngouamegne Tambou, M. Rohmer, S. Krasutsky, C.D. Poulter, V. Schünemann, M. Seemann
Biosynthesis of isoprene units: Mössbauer spectroscopy of substrate and inhibitor binding to the [4Fe-4S] cluster of the LytB/IspH enzyme.
Angew. Chem. Int. Ed.2011, 50, 11976-11979