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1. Experimental tuberculosis in the Wistar rat: a model for protective immunity and control of infection.

Author

Amit Singhal, El Moukhtar Aliouat, Maxime Hervé, Vanessa Mathys, Mehdi Kiass, Colette Creusy, Baptiste Delaire, Liana Tsenova, Laurence Fleurisse, Julie Bertout, Luis Camacho, Damian Foo, Hui Chien Tay, Jie Yee Siew, Warda Boukhouchi, Marta Romano, Barun Mathema, Véronique Dartois, Gilla Kaplan, and Pablo Bifani

Subjects
Medicine, Science
Abstract

BACKGROUND: Despite the availability of many animal models for tuberculosis (TB) research, there still exists a need for better understanding of the quiescent stage of disease observed in many humans. Here, we explored the use of the Wistar rat model for the study of protective immunity and control of Mycobacterium tuberculosis (Mtb) infection. METHODOLOGY/PRINCIPAL FINDINGS: The kinetics of bacillary growth, evaluated by the colony stimulating assay (CFU) and the extent of lung pathology in Mtb infected Wistar rats were dependent on the virulence of the strains and the size of the infecting inoculums. Bacillary growth control was associated with induction of T helper type 1 (Th1) activation, the magnitude of which was also Mtb strain and dose dependent. Histopathology analysis of the infected lungs demonstrated the formation of well organized granulomas comprising epithelioid cells, multinucleated giant cells and foamy macrophages surrounded by large numbers of lymphocytes. The late stage subclinical form of disease was reactivated by immunosuppression leading to increased lung CFU. CONCLUSION: The Wistar rat is a valuable model for better understanding host-pathogen interactions that result in control of Mtb infection and potentially establishment of latent TB. These properties together with the ease of manipulation, relatively low cost and well established use of rats in toxicology and pharmacokinetic analyses make the rat a good animal model for TB drug discovery.

Published
2011
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2. BCG induces protection against Mycobacterium tuberculosis infection in the Wistar rat model.

Author

Amit Singhal, Vanessa Mathys, Mehdi Kiass, Colette Creusy, Baptiste Delaire, El Moukhtar Aliouat, Véronique Dartois, Gilla Kaplan, and Pablo Bifani

Subjects
Medicine, Science
Abstract

Our understanding of the correlation of Mycobacterium bovis Bacille Calmette-Guerin (BCG)-mediated immune responses and protection against Mycobacterium tuberculosis (Mtb) infection is still limited. We have recently characterized a Wistar rat model of experimental tuberculosis (TB). In the present study, we evaluated the efficacy of BCG vaccination in this model. Upon Mtb challenge, BCG vaccinated rats controlled growth of the bacilli earlier than unvaccinated rats. Histopathology analysis of infected lungs demonstrated a reduced number of granulomatous lesions and lower parenchymal inflammation in vaccinated animals. Vaccine-mediated protection correlated with the rapid accumulation of antigen specific CD4(+) and CD8(+) T cells in the infected lungs. Immunohistochemistry further revealed higher number of CD8(+) cells in the pulmonary granulomas of vaccinated animals. Evaluation of pulmonary immune responses in vaccinated and Mtb infected rats by real time PCR at day 15 post-challenge showed reduced expression of genes responsible for negative regulation of Th1 immune responses. Thus, early protection observed in BCG vaccinated rats correlated with a similarly timed shift of immunity towards the Th1 type response. Our data support the importance of (i) the Th1-Th2 balance in the control of mycobacterial infection and (ii) the value of the Wistar rats in understanding the biology of TB.

Published
2011
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3. The small-molecule SMARt751 reverses Mycobacterium tuberculosis resistance to ethionamide in acute and chronic mouse models of tuberculosis

Author

Marion Flipo, Rosangela Frita, Marilyne Bourotte, María S. Martínez-Martínez, Markus Boesche, Gary W. Boyle, Geo Derimanov, Gerard Drewes, Pablo Gamallo, Sonja Ghidelli-Disse, Stephanie Gresham, Elena Jiménez, Jaime de Mercado, Esther Pérez-Herrán, Esther Porras-De Francisco, Joaquín Rullas, Patricia Casado, Florence Leroux, Catherine Piveteau, Mehdi Kiass, Vanessa Mathys, Karine Soetaert, Véronique Megalizzi, Abdalkarim Tanina, René Wintjens, Rudy Antoine, Priscille Brodin, Vincent Delorme, Martin Moune, Kamel Djaout, Stéphanie Slupek, Christian Kemmer, Marc Gitzinger, Lluis Ballell, Alfonso Mendoza-Losana, Sergio Lociuro, Benoit Deprez, David Barros-Aguirre, Modesto J. Remuiñán, Nicolas Willand, and Alain R. Baulard

Subjects
General Medicine
Abstract

The sensitivity of Mycobacterium tuberculosis , the pathogen that causes tuberculosis (TB), to antibiotic prodrugs is dependent on the efficacy of the activation process that transforms the prodrugs into their active antibacterial moieties. Various oxidases of M. tuberculosis have the potential to activate the prodrug ethionamide. Here, we used medicinal chemistry coupled with a phenotypic assay to select the N-acylated 4-phenylpiperidine compound series. The lead compound, SMARt751, interacted with the transcriptional regulator VirS of M. tuberculosis , which regulates the mymA operon encoding a monooxygenase that activates ethionamide. SMARt751 boosted the efficacy of ethionamide in vitro and in mouse models of acute and chronic TB. SMARt751 also restored full efficacy of ethionamide in mice infected with M. tuberculosis strains carrying mutations in the ethA gene, which cause ethionamide resistance in the clinic. SMARt751 was shown to be safe in tests conducted in vitro and in vivo. A model extrapolating animal pharmacokinetic and pharmacodynamic parameters to humans predicted that as little as 25 mg of SMARt751 daily would allow a fourfold reduction in the dose of ethionamide administered while retaining the same efficacy and reducing side effects.

Published
2022
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4. Reversion of antibiotic resistance in Mycobacterium tuberculosis by spiroisoxazoline SMARt-420

Author

Alexandre Wohlkonig, David Hot, Sebastien Gagneux, Marc Gitzinger, Julia Feldmann, Mireia Coscolla, Marion Flipo, Nicolas Willand, Martin Moune, Kamel Djaout, Mehdi Kiass, Priscille Brodin, Vincent Delorme, Vanessa Mathys, Rosangela Frita, Karine Soetaert, Benoit Deprez, Ludovic Huot, Nicolas Blondiaux, René Wintjens, Christian Kemmer, Alain R. Baulard, Vincent Trebosc, Camille Locht, Matthieu Desroses, Rudy Antoine, Willand, Nicolas, Appel à projets générique - Reprogrammation de la bioactivation des thioamides comme alternative antituberculeuse - - Tea-4-Two2014 - ANR-14-CE14-0027 - Appel à projets générique - VALID, Equipements d'excellence - Plateau de microscopie de criblage à haut débit et d'analyse à très haute résolution - - Imaginex BioMed2010 - ANR-10-EQPX-0004 - EQPX - VALID, EGID Diabetes Pole - - EGID2010 - ANR-10-LABX-0046 - LABX - VALID, Plate forme Lilloise de séquençage du génome humain pour une médecine personnalisée - - LIGAN PM2010 - ANR-10-EQPX-0007 - EQPX - VALID, A Chemical Genomics Approach of Intracellular Mycobacterium tuberculosis Towards Defining Specific Host Pathogen Interactions - INTRACELLTB - - EC:FP7:ERC2010-12-01 - 2015-11-30 - 260901 - VALID, Compensatory Evolution and Epistasis in Multidrug-resistant Mycobacterium tuberculosis - EVODRTB - - EC:FP7:ERC2013-04-01 - 2018-03-31 - 309540 - VALID, More Medicines for Tuberculosis - MM4TB - - EC:FP7:HEALTH2011-02-01 - 2016-01-31 - 260872 - VALID, Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Médicaments et molécules pour agir sur les Systèmes Vivants - U 1177 (M2SV), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Karolinska Institutet [Stockholm], Institut Scientifique de Santé Publique [Belgique] - Scientific Institute of Public Health [Belgium] (WIV-ISP), Réseau International des Instituts Pasteur (RIIP), Tuberculosis Lab [Korea], Institut Pasteur Korea - Institut Pasteur de Corée, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Bioversys AG [Basel], University of Basel (Unibas), Université libre de Bruxelles (ULB), VIB-VUB Center for Structural Biology [Bruxelles], VIB [Belgium], Vrije Universiteit Brussel [Bruxelles] (VUB), Swiss Tropical and Public Health Institute [Basel], This work was supported by l’Agence Nationale de la Recherche (ANR), France (Tea-4-Two, ANR-14-CE14-0027-01) (ANR-10-EQPX-04-01), by EU grants ERC-STG INTRACELLTB no 260901, the Feder (12001407 (D-AL), PRIM (NewBio4Tb), European Research Council (grant 309540-EVODRTB), SystemsX.ch, Institut National de la Santé et de la Recherche Médicale, Université de Lille, Institut Pasteur de Lille, Centre National de la Recherche Scientifique, the Région Hauts-de-France (convention no. 12000080), and Société d’Accélération du Transfert de Technologie Nord. R.W. is Research Associate at the National Fund for Scientific Research (FNRS-FRS) (Belgium). M.M. was supported by PRIM (NewBio4Tb), V.D. was supported by EU grant 260872, and V.T. was suppported by the Marie Curie Initial Training Network (ITN-2013-607694-Translocation). The authors also thank the Unité Mixte de Recherche UMR 8199, Lille Integrated Genomics Network for Advanced Personalized Medicine (LIGAN-PM) Genomics platform (Lille, France), which belongs to the Federation de Recherche 3508 Labex EGID (European Genomics Institute for Diabetes, ANR-10-LABX-46) and was supported by the Agence Nationale de la Recherche (ANR) Equipex 2010 session (ANR-10-EQPX-07-01, LIGAN-PM). The LIGAN-PM Genomics platform is supported by the Fonds Européen de Développement Régional and the Region Hauts-de-France., ANR-14-CE14-0027,Tea-4-Two,Reprogrammation de la bioactivation des thioamides comme alternative antituberculeuse(2014), ANR-10-EQPX-0004,Imaginex BioMed,Plateau de microscopie de criblage à haut débit et d'analyse à très haute résolution(2010), ANR-10-LABX-0046,EGID,EGID Diabetes Pole(2010), ANR-10-EQPX-0007,LIGAN PM,Plate forme Lilloise de séquençage du génome humain pour une médecine personnalisée(2010), European Project: 260901,EC:FP7:ERC,ERC-2010-StG_20091118,INTRACELLTB(2010), European Project: 309540,EC:FP7:ERC,ERC-2012-StG_20111109,EVODRTB(2013), European Project: 260872,EC:FP7:HEALTH,FP7-HEALTH-2010-single-stage,MM4TB(2011), and Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille

Subjects
0301 basic medicine, Tuberculosis, medicine.drug_class, [CHIM.THER] Chemical Sciences/Medicinal Chemistry, 030106 microbiology, Antibiotics, Reversion, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Microbiology, Mycobacterium tuberculosis, 03 medical and health sciences, Antibiotic resistance, [CHIM] Chemical Sciences, medicine, [CHIM]Chemical Sciences, chemistry.chemical_classification, Multidisciplinary, biology, medicine.disease, biology.organism_classification, 3. Good health, 030104 developmental biology, Enzyme, chemistry, Ethionamide, Bacteria, medicine.drug
Abstract

Countering TB prodrug resistance The arsenal of antibiotics for treating tuberculosis (TB) contains many prodrugs, such as ethionamide, which need activation by normal metabolism to release their toxic effects. Ethionamide is potentiated by small molecules. Blondiaux et al. screened for more potent analogs and identified a lead compound called SMARt-420. This small molecule inactivates a TetR-like repressor, EthR2, and boosts ethionamide activation. SMARt-420 successfully promoted clearance of multidrug-resistant strains of Mycobacterium tuberculosis from the lungs of mice. Science , this issue p. 1206

Published
2017
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5. Reversion of antibiotic resistance in

Author

Nicolas, Blondiaux, Martin, Moune, Matthieu, Desroses, Rosangela, Frita, Marion, Flipo, Vanessa, Mathys, Karine, Soetaert, Mehdi, Kiass, Vincent, Delorme, Kamel, Djaout, Vincent, Trebosc, Christian, Kemmer, René, Wintjens, Alexandre, Wohlkönig, Rudy, Antoine, Ludovic, Huot, David, Hot, Mireia, Coscolla, Julia, Feldmann, Sebastien, Gagneux, Camille, Locht, Priscille, Brodin, Marc, Gitzinger, Benoit, Déprez, Nicolas, Willand, and Alain R, Baulard

Subjects
Oxadiazoles, Extensively Drug-Resistant Tuberculosis, Antitubercular Agents, DNA, Isoxazoles, Mycobacterium tuberculosis, Repressor Proteins, Mice, Piperidines, Drug Resistance, Multiple, Bacterial, Mutation, Animals, Humans, Spiro Compounds, Ethionamide, Protein Binding
Abstract

Antibiotic resistance is one of the biggest threats to human health globally. Alarmingly, multidrug-resistant and extensively drug-resistant

Published
2016

6. Molecular Genetics of para -Aminosalicylic Acid Resistance in Clinical Isolates and Spontaneous Mutants of Mycobacterium tuberculosis

Author

Natalia Kurepina, Amit Singhal, René Wintjens, Philippe Lefèvre, Vanessa Mathys, Barry N. Kreiswirth, Mehdi Kiass, Xiao-Ming Wang, Alain R. Baulard, Julie Bertout, Pablo Bifani, and Barun Mathema

Subjects
Pharmacology, Genetics, medicine.medical_specialty, Mutation, biology, Mutant, Drug resistance, biology.organism_classification, medicine.disease_cause, Genetic analysis, Microbiology, Mycobacterium tuberculosis, Infectious Diseases, Mechanisms of Resistance, Molecular genetics, medicine, Pharmacology (medical), Gene, Antibacterial agent
Abstract

The emergence of Mycobacterium tuberculosis resistant to first-line antibiotics has renewed interest in second-line antitubercular agents. Here, we aimed to extend our understanding of the mechanisms underlying para-aminosalicylic acid (PAS) resistance by analysis of six genes of the folate metabolic pathway and biosynthesis of thymine nucleotides ( thyA, dfrA, folC, folP1, folP2 , and thyX ) and three N -acetyltransferase genes [ nhoA, aac(1) , and aac(2) ] among PAS-resistant clinical isolates and spontaneous mutants. Mutations in thyA were identified in only 37% of the clinical isolates and spontaneous mutants. Overall, 24 distinct mutations were identified in the thyA gene and 3 in the dfrA coding region. Based on structural bioinformatics techniques, the altered ThyA proteins were predicted to generate an unfolded or dysfunctional polypeptide. The MIC was determined by Bactec/Alert and dilution assay. Sixty-three percent of the PAS-resistant isolates had no mutations in the nine genes considered in this study, revealing that PAS resistance in M. tuberculosis involves mechanisms or targets other than those pertaining to the biosynthesis of thymine nucleotides. The alternative mechanism(s) or pathway(s) associated with PAS resistance appears to be PAS concentration dependent, in marked contrast to thyA -mutated PAS-resistant isolates.

Published
2009
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7. BCG induces protection against Mycobacterium tuberculosis infection in the Wistar rat model

Author

Mehdi Kiass, Baptiste Delaire, Véronique Dartois, Pablo Bifani, El Moukhtar Aliouat, Amit Singhal, Colette Creusy, Gilla Kaplan, and Vanessa Mathys

Subjects
CD4-Positive T-Lymphocytes, Tuberculosis, Immunology, lcsh:Medicine, CD8-Positive T-Lymphocytes, Mycobacterium tuberculosis, Immune system, Immunity, medicine, Animals, Cluster Analysis, Rats, Wistar, lcsh:Science, Lung, Biology, Immunity to Infections, Immune Response, Inflammation, Mycobacterium bovis, Multidisciplinary, Granuloma, biology, business.industry, lcsh:R, Interferon-alpha, Interferon-beta, Th1 Cells, medicine.disease, biology.organism_classification, Immunohistochemistry, Rats, Vaccination, Disease Models, Animal, BCG Vaccine, lcsh:Q, Female, Interleukin-4, business, BCG vaccine, Research Article
Abstract

Our understanding of the correlation of Mycobacterium bovis Bacille Calmette-Guerin (BCG)-mediated immune responses and protection against Mycobacterium tuberculosis (Mtb) infection is still limited. We have recently characterized a Wistar rat model of experimental tuberculosis (TB). In the present study, we evaluated the efficacy of BCG vaccination in this model. Upon Mtb challenge, BCG vaccinated rats controlled growth of the bacilli earlier than unvaccinated rats. Histopathology analysis of infected lungs demonstrated a reduced number of granulomatous lesions and lower parenchymal inflammation in vaccinated animals. Vaccine-mediated protection correlated with the rapid accumulation of antigen specific CD4(+) and CD8(+) T cells in the infected lungs. Immunohistochemistry further revealed higher number of CD8(+) cells in the pulmonary granulomas of vaccinated animals. Evaluation of pulmonary immune responses in vaccinated and Mtb infected rats by real time PCR at day 15 post-challenge showed reduced expression of genes responsible for negative regulation of Th1 immune responses. Thus, early protection observed in BCG vaccinated rats correlated with a similarly timed shift of immunity towards the Th1 type response. Our data support the importance of (i) the Th1-Th2 balance in the control of mycobacterial infection and (ii) the value of the Wistar rats in understanding the biology of TB.

Published
2011

8. Mycobacterium tuberculosis infection induces hypoxic lung lesions in the rat

Author

YiXiong Heng, Vanessa Mathys, Peck Gee Seah, Maxime Herve, Jie Yee Siew, Amit Singhal, Véronique Dartois, Hui Chien Tay, Mehdi Kiass, and Pablo Bifani

Subjects
Microbiology (medical), Pathology, medicine.medical_specialty, Tuberculosis, Immunology, Drug resistance, Biology, Microbiology, Mycobacterium tuberculosis, medicine, Pimonidazole, Animals, Pulmonary pathology, Hypoxia, Lung, Tuberculosis, Pulmonary, Granuloma, Hypoxia (medical), medicine.disease, biology.organism_classification, Immunohistochemistry, Rats, Disease Models, Animal, Infectious Diseases, medicine.anatomical_structure, Nitroimidazoles, Female, medicine.symptom
Abstract

Hypoxia is believed to influence the metabolic state of Mycobacterium tuberculosis and cause phenotypic drug resistance. Using pimonidazole adduct staining, we show that lung lesions of infected rats contain regions of low oxygen tension. Our results support the use of the rat model for evaluating anaerobic drug activity in vivo.

Published
2011

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