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The small-molecule SMARt751 reverses Mycobacterium tuberculosis resistance to ethionamide in acute and chronic mouse models of tuberculosis
Alain Baulard, Senior Research Scientist at Inserm, and researchers from Institut Pasteur de Lille, University of Lille, and a large public-private international consortium, published this week in Science Translational Medicine their progress in developing a highly innovative drug candidate that reverses ethionamide-resistance in the deadly human pathogen Mycobacterium tuberculosis.
French researchers at Institut Pasteur de Lille and University of Lille and their colleagues of a large public-private consortium including BioVersys and GSK are publishing today in Science Translational Medicine their progress in the development of a highly innovative drug-candidate that reverses ethionamide resistance in the deadly pathogen M. tuberculosis.
Tuberculosis (TB) has been a scourge of humankind for centuries and remains today a major infectious disease killer. Worldwide antibiotic campaigns have been essential to tackle the TB pandemic, but recently there has been a worrisome progression of antibiotic resistance that is now undermining these public health strategies.
Since the discovery of antibiotics, a continuous fight opposes humans and bacterial pathogens, the latter trying to escape the more and more sophisticated drugs developed by the former. At the origin of the fight described today in Science Translational Medicine by M. Flipo and colleagues, is ethionamide, which belongs to a peculiar family of anti-tuberculosis drugs called pro-antibiotics. Following their penetration into the bacteria, pro-antibiotics such as ethionamide are bioactivated by specific bacterial enzymes to produce derivatives that kill the bug.
In their permanent struggle to overcome the effects of antibiotics, some M. tuberculosis clinical strains are able to shut down the biochemical pathway responsible for ethionamide bioactivation.
The game could end here, but it is not the case. A first step forward in this fight was achieved by the team thanks to the identification of a small molecule called SMARt420 that up-regulates an alternative enzyme able to activate ethionamide in resistant bacteria, switching them back to being ethionamide sensitive.
In today's story, the authors describe a new version of their anti-TB weapon, with the discovery of the small molecule SMARt751 able to engage an additional, more efficient, ethionamide activation pathway.
Not only does SMARt751 overcome resistant strains, but it also drastically increases ethionamide potency on sensitive strains. SMARt751 is safe, and active in vivo against chronic TB in infected mice. Extrapolation of the results from mice to humans predicts that SMARt751 would be sufficient to lower the efficacious dose of ethionamide in humans by four-fold, which would drastically improve ethionamide’ tolerability.
Is the game over? Certainly not, as M. tuberculosis will, as always, fight back with alternative resistance mechanisms, but SMARt751 and its derivatives that are now in clinical development with our partners BioVersys and GSK are powerful weapons that can make the pathogen’s life significantly more difficult, and potentially offer patients a more efficacious and safer treatment option.
Investigating the micropumps behind antibiotic resistance
Juan-Carlos Jiménez Castellanos is a researcher at the Pasteur Institute in Lille, France. Credit: Lucas Barioulet for Nature
Antibiotic-resistant bacteria, especially those that are resistant to multiple drugs, pose a major threat to health globally; tackling them is a crucial research priority of the World Health Organization. I am a protein chemist and molecular biologist investigating why bacteria often refuse to die when attacked by antibiotics.
Bacteria can evade antibiotics in clever ways. One involves ejecting them through efflux pumps embedded in the bacterium’s inner membrane. These are like tiny vacuum cleaners that constantly flush out substances that are toxic to bacteria.
I’ve been fascinated by efflux pumps ever since my undergraduate studies in Mexico more than 16 years ago. I’m particularly interested in how they can bind to and extrude dozens of chemically unrelated compounds quickly, efficiently and simultaneously. I’m working on the hypothesis that they do this using a unique group of proteins that lack stable structures — known as intrinsically disordered proteins.
Here at the Pasteur Institute in Lille, France, I’m using advanced screening technology to test the ability of different molecules to inhibit the actions of efflux pumps. I’m helped by an automated circuit, with a range of experimental equipment, and a robot that can load up to 200 assay plates into a carousel. I can program in what I want and go for a coffee while the robot gets to work.
I find it amazing that the proteins in all life forms consist of different combinations of the same 20 amino acids. I can’t really describe why, but solving problems about proteins makes me so happy.
With colleagues, I’ve also been working to develop new efflux pump inhibitors (C. Plé et al. Nature Commun. 13, 115; 2022). My hope is that these can be used both to advance our understanding of how efflux pumps work and, with existing antibiotics, to counter antibiotic and multidrug resistance.
Future Investments" program Call for PPR projects "Antibiotic resistance: understand, innovate, act PPR-AMR-Edition 2021
Mustart — Multiparametric Strategies against Antibiotic Resistance in Tuberculosis
The reduction in the global incidence of tuberculosis (TB) observed each year is too small to compensate for the worrying increase in multidrug resistance to anti-tuberculosis drugs (MDR-TB). While Europe has the lowest incidence of TB in the world, it is also where the rate of MDR-TB is the highest. The worrisome dispersion of MDR strains in a growing population of latent healthy carriers, in which resistance cannot be detected to date, constitutes a major obstacle to WHO's eradication objectives.
In comparison to other bacterial infections, tuberculosis therapy is very long, going from months for completion, to even years in the case of MDR-TB. The length of this treatment reveals that the efficiency of current therapy is certainly not optimal, which can lead to lower compliance and the gradual selection of MDR or XDR tuberculosis.
A major reason why treating TB takes so long is probably because, in the body, M. tuberculosis resides in different (stochastic) physiological and metabolic forms, some of which are tolerant to many of the antibiotics in use. In this context, the recent burden of MDR-TB adds to the urgent need for combinations of novel antibiotic classes that target the mycobacteria in its various niches.
An additional drawback to tuberculosis therapy, and indeed to the efficient development of novel tuberculosis therapies, is that it is not possible to routinely define treatment efficacy in real time, neither are there tools to monitor the early emergence of subpopulations of drug resistance.
Nine French research teams are joining their expertise to tackle these questions through concerted and integrated research actions, from the laboratory to the patient's bedside. This consortium brings together seven powerful research teams specialized in TB (including two in Hospitals) as well as two partners from other fields providing new and complementary methodological approaches, making possible this ambitious and structuring project.
The consortium will share 9 innovative experimental compounds that have been identified for their ability to inhibit M. tuberculosis in at least one of its physiological niches, including by stimulating the response of the host to the infection. To complete this first objective, partners will share innovative screening models to enrich this list of potentially synergistic compounds. Combinations will be evaluated using ex vivo and in vivo models of infection in order to identify optimized multifaceted regimens.
This consortium has skills in microbiology, cell biology, immunology, biophysics, therapeutic chemistry, mathematics, biomedical resources, and most of all, the common will to carry out these objectives.
Alain Baulard, DR-Inserm
CIIL - Center for Infection and Immunity of Lille
Experts involved in the CIIL
Partner institution(s) involved in the project
1. CIIL - Institut Pasteur de Lille, Lille
2. IPBS, Toulouse
3. Sorbonne Université, Paris
4. U1177, Lille
5. IP, Paris
6. TBI, Toulouse
7. LMGM, Toulouse
8. CEA, Saclay
9. CIRI-HCL, Lyon
PIA —Programme Investissements d’Avenir 2021, Gestion ANR, Coordination Scientifique Inserm
More details on the ANR-AMR Initiative and the selected projects
For all internship applications, please send your request directly to the group leader of the research area that you are interested in :
1- Bacteria, Antibiotics & Immunity : Contact
2- Biology of Apicomplex Parasites : Contact
3- Cellular Microbiology & Physics of Infection : Contact
4- Chemical Biology of Antibiotics : Contact
5- Chemical Biology of Flatworms : Contact
6- Chemogenomics of Intracellular Mycobacteria : Contact
7- Ecology & Physiopathology of Intestinal Protozoa : Contact
8- Influenza, Immunity & Metabolism : Contact
9- Lung Immunity : Contact
10- Molecular & Cellular Virology : Contact
11- Opportunistic Infections, Immunity, Environment & Lung Diseases: Contact
12- Plague & Yersinia pestis : Contact
13- Research on Mycobacteria and Bordetella: Contact
14- Tropical Biomes & Immuno-Pathophysiology : Contact
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Third episode in the series dedicated to researching Covid-19. This webinar is moderated by Marie Treibert, science popularizer on the La Boîte à curiosités channel. She questions Sandrine Belouzard, virologist and CNRS researcher, who answers all questions relating to antivirals in the treatment of Covid-19. What is the difference between a vaccine and an antiviral treatment? How does an antiviral work? Who will benefit from it? Do we favor therapeutic repositioning or research for a new drug? Through definitions, a press review and an interview, this webinar takes stock of the subject.
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