MABA inhibitors

Team

  • Team Leader : Marion Flipo PhD - Assistant
  • Pr Nicolas Willand PhD - Professor
  • Hughes Prevet - PhD student
  • Catalin Pintiala PostDoc

Mission

Develop a fragment-based approach to discover drug-like inhibitors of MabA as a new strategy to treat tuberculosis.

Approach

Tuberculosis causes every year 1.4 million deaths worldwide therefore molecules that are active against unexploited targets are obviously needed. Mycolic acids are very long-chain fatty acids (C60–C90) playing an essential role in the architecture and permeability of the envelope of Mycobacterium tuberculosis. The front-line antibiotic isoniazid and several other drugs (ethionamide, isoxyl, thiacetazone and thiolactomycin) target the biosynthesis of mycolic acids and especially the Fatty Acid Synthase-II (FAS-II) elongation system. This biosynthetic pathway is essential and specific to mycobacteria and has proven a rich source of targets for antibiotics. The protein MabA, also named FabG1, is a key enzyme involved in this process that catalyses the NADPH-specific reduction of long chain β-ketoacyl derivatives. It has genetically been shown to be essential for M. tuberculosis survival and it represents a target of choice to start a drug discovery program.

The main objective of this project is to use a fragment-based drug design approach to find and optimize new low-molecular-weight inhibitors of MabA. These inhibitors will be useful to design novel therapies against tuberculosis and to overcome drug resistance.

Latest results

To enhance the chance to find low-molecular-weight inhibitors, with adequate physicochemical properties to penetrate into the mycobacteria and reach their target, we screened a 1040-fragment library that led to the identification of 82 hits and demonstrated the chemical tractability of MabA. In the next step, we will optimize these fragments to obtain potent compounds and to show that the pharmacological inhibition of MabA is bactericidal. Finally, we will optimize our inhibitors into lead compounds for an in vivo proof of concept.

National and International collaborations:

  • Alain Baulard INSERM U1019, CNRS UMR8204, Univ. Lille Nord de France, Institut Pasteur de Lille, 1 rue du Professeur Calmette, Lille F-59019 France.
  • Priscille Brodin INSERM U1019, CNRS UMR8204, Univ. Lille Nord de France, Institut Pasteur de Lille, 1 rue du Professeur Calmette, Lille F-59019 France.
  • Alexandre Wohlkönig Vlaams Instituut voor Biotechnologie (VIB), 1050 Brussels Belgium.
  • René Wintjens ULB, 1050 Brussels, Belgium.

Publications:

Articles

  • Kussau, T., Flipo, M., Van Wyk, N., Viljoen, A., Olieric, V., Kremer, L., & Blaise, M. Structural rearrangements occurring upon cofactor binding in the Mycobacterium smegmatis beta-ketoacyl-acyl carrier protein reductase MabA. Acta crystallographica. Section D, Structural biology,2018, 74(Pt 5): 383-393. 10.1107/s2059798318002917

Communications

Faion, L. Structural optimization and biological evaluation of Mycobacterium tuberculosis MabA inhibitors,19eme Journées André Verbert,Lille, France,10th Sept. 2019 Flashtalk.

Faion, L. Chemical modifications of Mycobacterium tuberculosis MabA inhibitors,2e Journée de la Recherche de la Faculté de Pharmacie,Lille, France,11th Jul 2018 flash presentation

Faïon, L., Pintiala, C., Moune, M., Frita, R., Djaout, K., Piveteau, C., Deprez, B., Baulard, A., Willand, N., & Flipo, M. Chemical modifications of Mycobacterium tuberculosis MabA inhibitors 25th Young reasearch fellow meeting of SCT, Orleans, France, 5th-7th March,2018.

Faion, L., Pintiala, M., Moune, M., Frita, R., Djaout, K., Piveteau, C., Deprez, B., Baulard, A., Willand, N., & Flipo, M. Chemical modifications of Mycobacterium tuberculosis MabA inhibitors 26th GP2A – 32nd JFB, Asnelles sur mer, France, 13th-15th Jun.,2018.

Faion, L., Pintiala, M., Moune, M., Frita, R., Djaout, K., Piveteau, C., Deprez, B., Baulard, A., Willand, N., & Flipo, M. Chemical modifications of Mycobacterium tuberculosis MabA inhibitors 2e Journée de la Recherche de la Faculté de Pharmacie, Lille, France, 11th Jul,2018.

Pintiala, C., Moune, M., Bourbiaux, K., Frita, R., Djaout, K., Piveteau, C., Deprez, B., Baulard, A., Willand, N., & Flipo, M. Discovery of the first low-molecular-weight Mycobacterium tuberculosis MabA (FabG1) inhibitors using a fragment-based approach 253rd ACS National Meeting,, San Francisco, CA, USA, , April 2nd-6th, 2017.

Pintiala, C., Moune, M., Bourbiaux, K., Frita, R., Djaout, K., Catherine, P., Deprez, B., Baulard, A., Willand, N., & Flipo, M. Discovery and optimization of Mycobacterium tuberculosis MabA inhibitors 24th Young Research Fellow Meeting of the SCT, Châtenay Malabry, France, 8th-10th February, 2017.

Tran Ngoc, C., Moune, M., A., B., Deprez, B., M., F., & Willand, N. Integrating Fragment-screening and Fragment-based drug design for the discovery of Mycobacterium tuberculosis MabA inhibitors XXIst Young Research Fellow Meeting of the SCT, Montpellier, France, 24th-25th Mar, 2014.

 

Posters

Faion, L., Pintiala, C., Moune, M., Djaout, K., Frita, R., Hanoulle, X., Cantrelle, F.-X., Piveteau, C., Deprez, B., Baulard, A., Willand, N., & M., F. Discovery, Optimization And Biological Evaluation Of The First Low-Molecular-Weight Mycobacterium Tuberculosis Maba (Fabg1) Inhibitors 55th International Conference on Medicinal Chemsitry (RICT), Nantes, France, 3rd-5th July,2019.

Faïon, L., Pintiala, C., Moune, M., Frita, R., Djaout, K., Piveteau, C., Deprez, B., Baulard, A., Willand, N., & Flipo, M. Structural optimization and biological evaluation of Mycobacterium tuberculosis MabA inhibitors 26th SCT Young Research Fellow Meeting, Paris, France, 20th-22nd Feb.,2019.

Faïon, L., Pintiala, C., Moune, M., Frita, R., Djaout, K., Piveteau, C., Deprez, B., Baulard, A., Willand, N., & Flipo, M. Chemical modifications of Mycobacterium tuberculosis MabA inhibitors 25th Young reasearch fellow meeting of SCT, Orleans, France, 5th-7th March,2018.

Faion, L., Pintiala, M., Moune, M., Frita, R., Djaout, K., Piveteau, C., Deprez, B., Baulard, A., Willand, N., & Flipo, M. Chemical modifications of Mycobacterium tuberculosis MabA inhibitors 26th GP2A – 32nd JFB, Asnelles sur mer, France, 13th-15th Jun.,2018.

Faion, L., Pintiala, M., Moune, M., Frita, R., Djaout, K., Piveteau, C., Deprez, B., Baulard, A., Willand, N., & Flipo, M. Chemical modifications of Mycobacterium tuberculosis MabA inhibitors 2e Journée de la Recherche de la Faculté de Pharmacie, Lille, France, 11th Jul,2018.

Faion, L., Pintiala, C., Moune, M., Frita, R., Djaout, K., Piveteau, C., Deprez, B., Baulard, A., Willand, N., & Flipo, M. Optimization of MabA inhibitors as an innovative strategy to fight tuberculosis Drug discovery Day-Master Seminar, School of Pharmacy, Lille, France, 7th Dec.,2017.

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