Tuberculosis and antibiotic resistance: the Institut Pasteur in Lille leads a research to develop a

The Institut Pasteur in Lille leads a research to develop a new prototype drug

Researchers from the Institut Pasteur in Lille, France and their co-workers (including a scientist from the Institut Pasteur Korea)* have developed a drug candidate able to reverse resistance to ethionamide, an antibiotic used to treat tuberculosis. They have published their work in Science (17 March 2017), bringing a strong contribution in the global fight against antibiotic resistance. Like many antitubercular drugs, ethionamide is a pro antibiotic. These drugs have to be activated inside the bacteria before they can be able to kill the pathogen. Resistance to ethionamide occurs when mutations alter the bioactivation process. « Through the close interactions between our teams of biologists and medicinal chemists, we have succeeded in designing a prototype molecule - SMARt-420 - that triggers a new bioactivation pathway of ethionamide. This causes a full resensitisation of bacteria with ethionamide-acquired resistance. » Dr Alain Baulard (Center for Infection and Immunity of Lille, Institut Pasteur/Inserm/CNRS/Université de Lille) and Prof Nicolas Willand say (Drugs and Molecules for Living Systems Unit, Insitut Pasteur/Inserm/Université de Lille). Combination of both SMARt-420 and ethionanamide has enabled to efficiently treat mice infected with tuberculosis bacilli that has become resistant to the sole antibiotic. This work paves the way to a new drug candidate, currently being developed in partnership with GlaxoSmithKline (GSK) and Bioversys.

The publication: Reversion of antibiotic resistance in Mycobacterium tuberculosis by spiroisoxazoline SMARt-420, Science. 2017 Mar 17;355(6330):1206-1211. doi: 10.1126/science.aag1006 Blondiaux N, Moune M, Desroses M, Frita R, Flipo M, Mathys V, Soetaert K, Kiass M, Delorme V, Djaout K, Trebosc V, Kemmer C, Wintjens R, Wohlkönig A, Antoine R, Huot L, Hot D, Coscolla M, Feldmann J, Gagneux S, Locht C, Brodin P, Gitzinger M, Déprez B, Willand N, Baulard AR.

* Université de Lille (France), French National Center for Scientific Research (CNRS), French National Institute of Health and Medical Research (Inserm), Karolinska Institutet (Stockholm, Sweden), Scientific Institute of Public Health (WIV-ISP, Brussels, Belgium), Tuberculosis Research Laboratory at the Institut Pasteur Korea, Bioversys AG (Switzerland), University of Basel (Switzerland), Université Libre de Bruxelles (Brussels, Belgium), VIB Center for Structural Biology (Brussels, Belgium), Swiss Tropical and Public Health Institute (Basel, Switzerland).

From Inserm press release, 16 March 2017, in French.