Tricyclic SpiroLactams Kill Mycobacteria in vitro and in vivo by Inhibiting Type II NADH Dehydrogenases
Despite the availability of antibiotics and vaccines, Mycobacterium tuberculosis remains the leading cause of death by a bacterial pathogen in the world, responsible for approximatively 1.5 million deaths per year.
While treatment of tuberculosis with multidrug therapy is already lengthy a 6 month, increasing prevalence of multidrug resistant tuberculosis makes their treatment even more challenging and much longer (up to 2 years). With the aim of making an impact on anti-tuberculosis therapy, the research teams of Ruben Hartkoorn (CIIL, INSERM U1019, CNRS UMR9017, Univ. Lille, IPL), Nicolas Willand and Baptiste Villemagne (M2SV, U1177 Inserm, Univ. Lille, IPL) joint forces to discover and develop novel anti-tuberculosis molecules from a collection of unique synthetic biomimetic compounds from the chemical library of Institut Pasteur de Lille. This collaborative effort allowed for the identification and development of a novel class of antibiotics named TriSLa, that target a previously unexploited protein of the bacterial electron transport chain (energy/ATP generation pathway), named type-II NADH dehydrogenase. In collaboration with the research team of Laurent Kremer (IRIM, INSERM U119, UMR 9004-CNRS, Université de Montpellier), it could be demonstrated that these TriSLa molecules are able to protect zebrafish from a mycobacterial infection (“fish tuberculosis”), confirming for the first time efficacy of such a class of antibiotics in an animal model. This work (Dam, Tangara & Hamela at al.) has been published in a high impact scientific journal, the Journal of Medicinal Chemistry, and brings to light an exciting novel class of anti-tuberculosis molecules that has the potential of contributing to the fight against tuberculosis in the future.
This project was supported by ATIP-Avenir, by ANR (ANR-19-CE18-0034-01), by European Union under the European Regional Development Fund (ERDF), by the Hauts De France Regional Council (Contracts n°NP0020070 and n°20002842), by the MEL (contract_2020_ESR_06), by the French state (contract n°2020-R3-CTRL_IPL_Phase4) and by I-Site ULNE (ANR-16-IDEX-0004 ULNE).
Sushovan Dam#, Salia Tangara#, Claire Hamela# (co-premiere), Theo Hattabi, Léo Faïon, Paul Carre, Rudy Antoine, Adrien Herledan, Florence Leroux, Catherine Piveteau, Maxime Eveque, Marion Flipo, Benoit Deprez, Laurent Kremer, Nicolas Willand, Baptiste Villemagne, Ruben C. Hartkoorn
J. Med. Chem. (open access) : HERE