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1. Rv0579 Is Involved in the Resistance to the TP053 Antitubercular Prodrug

Author

Giovanna Riccardi, Laurent R. Chiarelli, Vadim Makarov, Maria Rosalia Pasca, Beatrice Silvia Orena, Josè Camilla Sammartino, Giulia Degiacomi, Giorgia Mori, and Olga Riabova

Subjects
Microbiology (medical), Tuberculosis, Population, Mutant, lcsh:QR1-502, Drug resistance, Microbiology, lcsh:Microbiology, Rv0579, Mycobacterium tuberculosis, 03 medical and health sciences, medicine, education, Pathogen, 030304 developmental biology, Original Research, 0303 health sciences, education.field_of_study, drug resistance, biology, Latent tuberculosis, 030306 microbiology, Prodrug, biology.organism_classification, medicine.disease, 3. Good health, tuberculosis, antitubercular drug, prodrug
Abstract

Tuberculosis remains one of the leading causes of death from a single pathogen globally. It is estimated that 1/4 of the world’s population harbors latent tuberculosis, but only a 5–10% of patients will develop active disease. During latent infection, Mycobacterium tuberculosis can persist unaffected by drugs for years in a non-replicating state with low metabolic activity. The rate of the successful tuberculosis treatment is curbed by the presence of these non-replicating bacilli that can resuscitate after decades and also by the spread of M. tuberculosis drug-resistant strains. International agencies, including the World Health Organization, urge the international community to combat this global health emergency. The thienopyrimidine TP053 is a promising new antitubercular lead compound highly active against both replicating and non-replicating M. tuberculosis cells, with an in vitro MIC of 0.125 μg/ml. TP053 is a prodrug activated by the reduced form of the mycothiol-dependent reductase Mrx2, encoded by Rv2466c gene. After its activation, TP053 releases nitric oxide and a highly reactive metabolite, explaining its activity also against M. tuberculosis non-replicating cells. In this work, a new mechanism of TP053 resistance was discovered. M. tuberculosis spontaneous mutants resistant to TP053 were isolated harboring the mutation L240V in Rv0579, a protein with unknown function, but without mutation in Rv2466c gene. Recombineering method demonstrated that this mutation is linked to TP053 resistance. To better characterize Rv0579, the protein was recombinantly produced in Escherichia coli and a direct interaction between the Mrx2 activated TP053 and Rv0579 was shown by an innovative target-fishing experiment based on click chemistry. Thanks to achieved results, a possible contribution of Rv0579 in M. tuberculosis RNA metabolism was hypothesized, linked to toxin anti-toxin system. Overall, these data confirm the role of Rv0579 in TP053 resistance and consequently in the metabolism of this prodrug.

Published
2019

2. Synthesis, oxidation potential and anti-mycobacterial activity of isoniazid and analogues: insights into the molecular isoniazid activation mechanism

Author

Céline Deraeve, Giorgia Mori, Jean-Luc Stigliani, Alix Sournia-Saquet, Julie Laborde, Lea Lecoq, Beatrice Silvia Orena, Geneviève Pratviel, Vania Bernardes-Génisson, Laboratoire de chimie de coordination (LCC), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Dipartimento di Biologia e Biotecnologie ‘Lazzaro Spallanzani’, University of Pavia, and University of Pavia

Subjects
Tuberculosis, Drug resistance, 010402 general chemistry, medicine.disease_cause, 01 natural sciences, Mycobacterium tuberculosis, chemistry.chemical_compound, medicine, [CHIM.COOR]Chemical Sciences/Coordination chemistry, Heme, chemistry.chemical_classification, Mutation, biology, 010405 organic chemistry, Activator (genetics), Chemistry, Isoniazid, General Chemistry, biochemical phenomena, metabolism, and nutrition, respiratory system, bacterial infections and mycoses, biology.organism_classification, medicine.disease, 0104 chemical sciences, 3. Good health, Enzyme, Biochemistry, medicine.drug
Abstract

International audience; Tuberculosis (TB) is one of the leading causes of death due to infectious diseases. Among the specific drugs currently employed to treat tuberculosis, isoniazid (INH), a pro-drug, attracts a great interest. However, Mycobacterium tuberculosis (MTB) clinical isolates resistant to INH are significantly increasing thus compromising the efficiency of TB-treatment. Concerning the mechanism of resistance to INH, it is nowadays well established that it mainly results from mutations in the katG genes encoding for INH enzymatic activator. Recently, it was proposed that mutation in katG induces differences in heme or side chain redox potential so that the enzyme loses its ability to oxidize INH to radical species. In this work, we synthesized and selected a series of INH analogues for a study of their oxidation potential and evaluation of their anti-TB efficiency toward MTB wild-type and drug resistant strains. On the contrary to what was postulated, no correlation exists between the easier oxidation of a molecule and its anti-MTB activity toward resistant strains. Based on experimental data and theoretical calculations, we proposed an activation mechanism for INH and analogues based on a one-electron oxidation step of the hydrazyl function at the proximal nitrogen followed by a radical transposition to the distal nitrogen, which then induces a β-homolytic cleavage of the C(=O)-N bond to afford diazene and the isonicotinoyl radical species.

Published
2016
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3. Design, Syntheses, and Anti-TB Activity of 1,3-Benzothiazinone Azide and Click Chemistry Products Inspired by BTZ043

Author

Rohit Tiwari, Katarína Mikušová, Giorgia Mori, Michal Šarkan, Allen G. Oliver, Laurent R. Chiarelli, Scott G. Franzblau, Ivana Centárová, Marvin J. Miller, Patricia A. Miller, and Sang-Hyun Cho

Subjects
chemistry.chemical_classification, biology, 010405 organic chemistry, Stereochemistry, Mycobacterium smegmatis, Organic Chemistry, 010402 general chemistry, biology.organism_classification, 01 natural sciences, Biochemistry, Combinatorial chemistry, 0104 chemical sciences, 3. Good health, law.invention, chemistry.chemical_compound, Enzyme, chemistry, Nucleophile, Docking (molecular), law, Drug Discovery, Click chemistry, Recombinant DNA, Azide, Cell envelope
Abstract

Electron deficient nitroaromatic compounds such as BTZ043 and its closest congener, PBTZ169, and related agents are a promising new class of anti-TB compounds. Herein we report the design and syntheses of 1,3-benzothiazinone azide (BTZ-N3) and related click chemistry products based on the molecular mode of activation of BTZ043. Our computational docking studies indicate that BTZ-N3 binds in the essentially same pocket as that of BTZ043. Detailed biochemical studies with cell envelope enzyme fractions of Mycobacterium smegmatis combined with our model biochemical reactivity studies with nucleophiles indicated that, in contrast to BTZ043, the azide analogue may have a different mode of activation for anti-TB activity. Subsequent enzymatic studies with recombinant DprE1 from Mtb followed by MIC determination in NTB1 strain of Mtb (harboring Cys387Ser mutation in DprE1 and is BTZ043 resistant) unequivocally indicated that BTZ-N3 is an effective reversible and noncovalent inhibitor of DprE1.

Published
2016
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4. Evaluation of heteroatom-rich derivatives as antitubercular agents with InhA inhibition properties

Author

Christian Lherbet, Mohamed Amari, Beatrice Silvia Orena, Frédéric Rodriguez, Mokhtar Fodili, Nadji Belkheiri, Bachar Rébat Moulkrere, Nathalie Saffon-Merceron, Giorgia Mori, Pascal Hoffmann, Dipartimento di Biologia e Biotecnologie ‘Lazzaro Spallanzani’, University of Pavia, University of Pavia, Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC), Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique (SPCMIB), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), and Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, chemistry.chemical_classification, biology, 010405 organic chemistry, Chemistry, Stereochemistry, INHA, Organic Chemistry, Heteroatom, Fatty Acid Biosynthesis Pathway, Pharmacology toxicology, biology.organism_classification, 01 natural sciences, 3. Good health, 0104 chemical sciences, Mycobacterium tuberculosis, 03 medical and health sciences, 030104 developmental biology, Enzyme, Docking (molecular), [CHIM]Chemical Sciences, General Pharmacology, Toxicology and Pharmaceutics, ComputingMilieux_MISCELLANEOUS
Abstract

Two series of heterocyclic compounds derived from 3-acetyl-4-hydroxy-6-methyl-2H-pyran-2-one (DHA) and 2-acetylbutyrolactone have been synthesized and characterized. The compounds were evaluated for their activities against Mycobacterium tuberculosis strain, and as inhibitors of InhA, a key enzyme involved in the type II fatty acid biosynthesis pathway of M. tuberculosis. Among the tested compounds, one DHA derivative, compound 2, showed promising activity against both mycobacteria and InhA. Docking studies were also carried out and give some new structure-activity trends compatible with current structural knowledge.

Published
2018
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5. Mechanochemical Synthesis and Biological Evaluation of Novel Isoniazid Derivatives with Potent Antitubercular Activity

Author

Jan Madacki, Christian Lherbet, Michel Baltas, Laurent R. Chiarelli, Beatrice Silvia Orena, Maria Rosalia Pasca, Chantal Carayon, Jana Korduláková, Stéphane Massou, Christiane André-Barrès, Alain Chamayou, Paulo F.M. Oliveira, Brigitte Guidetti, Michel Baron, Giorgia Mori, Centre de recherche d'Albi en génie des procédés des solides divisés, de l'énergie et de l'environnement (RAPSODEE), Centre National de la Recherche Scientifique (CNRS)-IMT École nationale supérieure des Mines d'Albi-Carmaux (IMT Mines Albi), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique (SPCMIB), Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Comenius University in Bratislava, Università degli Studi di Pavia = University of Pavia (UNIPV), Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées, University of Pavia, IMT École nationale supérieure des Mines d'Albi-Carmaux (IMT Mines Albi), and Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Models, Molecular, Magnetic Resonance Spectroscopy, Antitubercular Agents, Molecular Conformation, Pharmaceutical Science, Hydrazone, 01 natural sciences, Analytical Chemistry, [SPI]Engineering Sciences [physics], Drug Discovery, chemistry.chemical_classification, Cell Death, biology, INHA, Hydrolysis, Isoniazid, Hydrogen-Ion Concentration, 3. Good health, Chemistry (miscellaneous), Thermodynamics, Molecular Medicine, medicine.symptom, Selectivity, medicine.drug, Stereochemistry, Microbial Sensitivity Tests, 010402 general chemistry, Article, Cell Line, Mycobacterium tuberculosis, lcsh:QD241-441, Isomerism, hydrazone, lcsh:Organic chemistry, medicine, Humans, Physical and Theoretical Chemistry, mechanochemistry, 010405 organic chemistry, Cell growth, Organic Chemistry, Hydrazones, biology.organism_classification, 0104 chemical sciences, Mechanism of action, chemistry, Quantum Theory, Spectrophotometry, Ultraviolet, Chromatography, Thin Layer
Abstract

International audience; A series of isoniazid derivatives bearing a phenolic or heteroaromatic coupled frame were obtained by mechanochemical means. Their pH stability and their structural (conformer/isomer) analysis were checked. The activity of prepared derivatives against Mycobacterium tuberculosis cell growth was evaluated. Some compounds such as phenolic hydrazine 1a and almost all heteroaromatic ones, especially 2, 5 and 7, are more active than isoniazid, and their activity against some M. tuberculosis MDR clinical isolates was determined. Compounds 1a and 7 present a selectivity index > 1400 evaluated on MRC5 human fibroblast cells. The mechanism of action of selected hydrazones was demonstrated to block mycolic acid synthesis due to InhA inhibition inside the mycobacterial cell.

Published
2017
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6. A Phenotypic Based Target Screening Approach Delivers New Antitubercular CTP Synthetase Inhibitors

Author

Laurent R. Chiarelli, David Barros, Júlia Zemanová, Marta Esposito, Beatrice Silvia Orena, Lluis Ballell, Francesca Boldrin, Sára Szadocka, Katarína Mikušová, Maria Rosalia Pasca, Giorgia Mori, Giulia Degiacomi, Sean Ekins, Giovanna Riccardi, Riccardo Manganelli, Valentina Piano, Stanislav Huszár, Andrea Mattevi, and Joël Lelièvre

Subjects
0301 basic medicine, Models, Molecular, medicine.drug_class, Pyridines, Phenotypic screening, 030106 microbiology, Antitubercular Agents, Gene Expression, Context (language use), Microbial Sensitivity Tests, Biology, Antimycobacterial, Binding, Competitive, Mycobacterium tuberculosis, Small Molecule Libraries, 03 medical and health sciences, Structure-Activity Relationship, Adenosine Triphosphate, Competitive, Bacterial Proteins, Models, Drug Discovery, medicine, Structure–activity relationship, Carbon-Nitrogen Ligases, Binding site, CTP synthetase, Enzyme Inhibitors, Drug discovery, phenotypic screening, Molecular, Binding, biology.organism_classification, Lipids, 3. Good health, High-Throughput Screening Assays, Molecular Docking Simulation, Kinetics, Thiazoles, 030104 developmental biology, Infectious Diseases, Biochemistry, target-based screening, biology.protein, drug discovery, pyridine-thiazole, Protein Binding
Abstract

Despite its great potential, the target-based approach has been mostly unsuccessful in tuberculosis drug discovery, while whole cell phenotypic screening has delivered several active compounds. However, for many of these hits, the cellular target has not yet been identified, thus preventing further target-based optimization of the compounds. In this context, the newly validated drug target CTP synthetase PyrG was exploited to assess a target-based approach of already known, but untargeted, antimycobacterial compounds. To this purpose the publically available GlaxoSmithKline antimycobacterial compound set was assayed, uncovering a series of 4-(pyridin-2-yl)thiazole derivatives which efficiently inhibit the Mycobacterium tuberculosis PyrG enzyme activity, one of them showing low activity against the human CTP synthetase. The three best compounds were ATP binding site competitive inhibitors, with Ki values ranging from 3 to 20 μM, but did not show any activity against a small panel of different prokaryotic a...

Published
2017

7. 2-Carboxyquinoxalines Kill Mycobacterium tuberculosis through Noncovalent Inhibition of DprE1

Author

Vadim Makarov, Antonio Carta, Maria Rosalia Pasca, Vincent Delorme, Gaëlle S. Kolly, Claudia Binda, Stewart T. Cole, Alessio Porta, Florence Pojer, Ramakrishna Gadupudi, Priscille Brodin, Ana Luisa de Jesus Lopes Ribeiro, Giuseppe Zanoni, Neeraj Dhar, Laurent R. Chiarelli, Valérie Landry, Svetlana Savina, Rosaria Luciani, Edda De Rossi, Davide Salvatore Francesco Farina, Giorgia Mori, Maria Paola Costi, Stefania Ferrari, Elisabetta Molteni, Alberto Venturelli, Giovanna Riccardi, João Neres, Puneet Saxena, and Ruben C. Hartkoorn

Subjects
Models, Molecular, quinoxaline derivatives, tuberculosis infections, enzyme inhibitors, Phenotypic screening, Mutant, Antitubercular Agents, Gene Expression, DprE1, Mutagenesis (molecular biology technique), Microbial Sensitivity Tests, Biology, Crystallography, X-Ray, Biochemistry, Protein Structure, Secondary, Rv3406, Small Molecule Libraries, Mycobacterium tuberculosis, Structure-Activity Relationship, Bacterial Proteins, Cell Wall, Quinoxalines, Drug Discovery, medicine, Enzyme Inhibitors, Gene, x-ray crystallography, mycobacterium tuberculosis, Oxidase test, Binding Sites, drug resistance, Intracellular parasite, Hydrogen Bonding, General Medicine, biology.organism_classification, Recombinant Proteins, Protein Structure, Tertiary, 3. Good health, Alcohol Oxidoreductases, Mechanism of action, Mutation, Molecular Medicine, medicine.symptom, mutagenesis, Protein Binding, tuberculosis infections, drug resistance, mutagenesis, x-ray crystallography, DprE1, Rv3406, enzyme inhibitors, quinoxaline derivatives, mycobacterium tuberculosis
Abstract

Phenotypic screening of a quinoxaline library against replicating Mycobacterium tuberculosis led to the identification of lead compound Ty38c (3-((4-methoxybenzyl)amino)-6-(trifluoromethyl)quinoxaline-2-carboxylic acid). With an MIC99 and MBC of 3.1 mu M, Ty38c is bactericidal and active against intracellular bacteria. To investigate its mechanism of action, we isolated mutants resistant to Ty38c and sequenced their genomes. Mutations were found in rv3405c, coding for the transcriptional repressor of the divergently expressed rv3406 gene. Biochemical studies clearly showed that Rv3406 decarboxylates Ty38c into its inactive keto metabolite. The actual target was then identified by isolating Ty38c-resistant mutants of an M. tuberculosis strain lacking rv3406. Here, mutations were found in dprE1, encoding the decaprenylphosphoryl-d-ribose oxidase DprE1, essential for biogenesis of the mycobacterial cell wall. Genetics, biochemical validation, and X-ray crystallography revealed Ty38c to be a noncovalent, noncompetitive DprE1 inhibitor. Structure-activity relationship studies generated a family of DprE1 inhibitors with a range of IC(50)s and bactericidal activity. Co-crystal structures of DprE1 in complex with eight different quinoxaline analogs provided a high-resolution interaction map of the active site of this extremely vulnerable target in M. tuberculosis.

Published
2014
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8. Pyrrolidinone and pyrrolidine derivatives: Evaluation as inhibitors of InhA and Mycobacterium tuberculosis

Author

Tetiana Matviiuk, Christian Lherbet, Michel Baltas, Andrii I. Kysil, Christophe Menendez, Maria Rosalia Pasca, Frédéric Rodriguez, Beatrice Silvia Orena, Giorgia Mori, Zoia Voitenko, Jan Madacki, Christiane André-Barrès, Sonia Mallet-Ladeira, Jana Korduláková, Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique (SPCMIB), Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Department of Biochemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Comenius University in Bratislava, Dipartimento di Biologia e Biotecnologie ‘Lazzaro Spallanzani’, University of Pavia, University of Pavia, Taras Shevchenko National University of Kyiv, and Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)

Subjects
0301 basic medicine, Pyrrolidines, Stereochemistry, Protein Conformation, Antitubercular Agents, Drug Evaluation, Preclinical, Microbial Sensitivity Tests, 01 natural sciences, Pyrrolidine, Mycobacterium tuberculosis, 03 medical and health sciences, chemistry.chemical_compound, Structure-Activity Relationship, Bacterial Proteins, Drug Discovery, Escherichia coli, [CHIM]Chemical Sciences, Enzyme Inhibitors, Mode of action, ComputingMilieux_MISCELLANEOUS, Pharmacology, biology, 010405 organic chemistry, INHA, Organic Chemistry, Membrane Transport Proteins, General Medicine, biology.organism_classification, Pyrrolidinones, 0104 chemical sciences, 3. Good health, Molecular Docking Simulation, 030104 developmental biology, chemistry, Biochemistry, Drug Design, Oxidoreductases
Abstract

A series of GEQ analogues bearing pyrrolidinone or pyrrolidine cores were synthesized and evaluated against InhA, essential target for Mycobacterium tuberculosis (M.tb) survival. The compounds were also evaluated against M.tb H37Rv growth. Interestingly, some of the compounds, not efficient as InhA inhibitors, are active against M.tb with MICs up to 1.4 μM. In particular, compound 4b was screened with different M.tb mutated strains in order to identify the cellular target, but without success, suggesting a new possible mode of action.

Published
2016
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9. Triazolophthalazines: Easily Accessible Compounds with Potent Antitubercular Activity

Author

Michel Baltas, Valérie Lobjois, Serhii Krykun, Damien Veau, Christian Lherbet, Giorgia Mori, Céline Frongia, Beatrice Silvia Orena, Stefan Chassaing, Maria Rosalia Pasca, Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique (SPCMIB), Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Dipartimento di Biologia e Biotecnologie ‘Lazzaro Spallanzani’, University of Pavia, University of Pavia, Institut des Technologies Avancées en sciences du Vivant (ITAV), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération (LBCMCP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Tuberculosis, medicine.drug_class, Stereochemistry, Cell Survival, Antitubercular Agents, Microbial Sensitivity Tests, Antimycobacterial, 01 natural sciences, Biochemistry, Mycobacterium tuberculosis, chemistry.chemical_compound, Minimum inhibitory concentration, Drug Discovery, Drug Resistance, Bacterial, medicine, Humans, [CHIM]Chemical Sciences, General Pharmacology, Toxicology and Pharmaceutics, Cytotoxicity, Cell survival, ComputingMilieux_MISCELLANEOUS, Pharmacology, biology, 010405 organic chemistry, Organic Chemistry, biology.organism_classification, medicine.disease, HCT116 Cells, 3. Good health, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, chemistry, Hydralazine Hydrochloride, Cinnamates, Molecular Medicine, Phthalazines, Organic synthesis
Abstract

Tuberculosis (TB) remains one of the major causes of death worldwide, in particular because of the emergence of multidrug-resistant TB. Herein we explored the potential of an alternative class of molecules as anti-TB agents. Thus, a series of novel 3-substituted triazolophthalazines was quickly and easily prepared from commercial hydralazine hydrochloride as starting material and were further evaluated for their antimycobacterial activities and cytotoxicities. Four of the synthesized compounds were found to effectively inhibit the Mycobacterium tuberculosis (M.tb) H37 Rv strain with minimum inhibitory concentration (MIC) values10 μg mL(-1) , whereas no compounds displayed cytotoxicity against HCT116 human cell lines (IC50100 μm). More remarkably, the most potent compounds proved to be active to a similar extent against various multidrug-resistant M.tb strains, thus uncovering a mode of action distinct from that of standard antitubercular agents. Overall, their ease of preparation, combined with their attractive antimycobacterial activities, make such triazolophthalazine-based derivatives promising leads for further development.

Published
2016
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10. Evaluation of the inhibitory activity of (aza)isoindolinone-type compounds: toward in vitro InhA action, Mycobacterium tuberculosis growth and mycolic acid biosynthesis

Author

Jean-Luc Stigliani, Vania Bernardes-Génisson, Maria Rosalia Pasca, Geneviève Pratviel, Giorgia Mori, Jean Bernadou, Annaïk Quémard, Christian Lherbet, Patricia Constant, Aurélien Chollet, Laboratoire de chimie de coordination (LCC), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique (SPCMIB), Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Dipartimento di Biologia e Biotecnologie ‘Lazzaro Spallanzani’, University of Pavia, University of Pavia, Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Dipartimento di Biologia e Biotecnologie 'Lazzaro Spallanzani' = Department of Biology and Biotechnology [Univ di Pavia] (DBB UNIPV), Università degli Studi di Pavia = University of Pavia (UNIPV), Université Toulouse III - Paul Sabatier (UT3), and Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Antitubercular Agents, Reductase, Isoindoles, 010402 general chemistry, 01 natural sciences, Biochemistry, law.invention, Mycobacterium tuberculosis, (aza)isoindolinone, mycolic acid biosynthesis, Structure-Activity Relationship, Bacterial Proteins, law, Drug Discovery, Structure–activity relationship, [CHIM.COOR]Chemical Sciences/Coordination chemistry, Binding site, Pharmacology, Binding Sites, biology, 010405 organic chemistry, Chemistry, INHA, Organic Chemistry, biology.organism_classification, Enoyl-(Acyl-Carrier-Protein) Reductase (NADH), In vitro, Recombinant Proteins, 0104 chemical sciences, 3. Good health, Protein Structure, Tertiary, Molecular Docking Simulation, Mycolic Acids, Docking (molecular), docking, Recombinant DNA, Molecular Medicine, InhA inhibition, Thermodynamics
Abstract

International audience; Inhibitors of the Mycobacterium tuberculosis enoyl-ACP reductase (InhA) are considered as potential promising therapeutics for the treatment of tuberculosis. Previously, we reported that azaisoindolinone-type compounds displayed, in vitro, inhibitory activity toward InhA. Herein, we describe chemical modifications of azaisoindolinone scaffold, the synthesis of 15 new compounds and their evaluations toward the in vitro InhA activity. Based on these results, a structure-InhA inhibitory activity relationship analysis and a molecular docking study, using the conformation of InhA found in the 2H7M crystal structure, were carried out to predict a possible mode of interaction of the best (aza)isoindolinone-type inhibitors with InhA in vitro. Then, the work was extended toward evaluations of these compounds against Mycobacterium tuberculosis (Mtb) growth, and finally, some of them were also investigated in respect of their ability to inhibit mycolic acid biosynthesis inside mycobacteria. Although, some azaisoindolinones were able to inhibit InhA activity and Mtb growth in vitro, they did not inhibit the mycolic acid biosynthesis inside Mtb.

Published
2016
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11. Thiophenecarboxamide Derivatives Activated by EthA Kill Mycobacterium tuberculosis by Inhibiting the CTP Synthetase PyrG

Author

Ana Luisa de Jesus Lopes Ribeiro, Maria Rosalia Pasca, Laurent R. Chiarelli, Giulia Degiacomi, Nathalie Barilone, Marco Fondi, Vadim Makarov, Leonardo B. Marino, Riccardo Manganelli, Marco Bellinzoni, Giuseppe Zanoni, Stewart T. Cole, Francesca Boldrin, Renato Fani, Alessio Porta, Giorgia Mori, Alain R. Baulard, Ruben C. Hartkoorn, Giovanna Riccardi, Jaroslav Blaško, Luiz Pedro S. de Carvalho, Pedro M. Alzari, Zuzana Svetlíková, Ivana Centárová, Elena Kazakova, Sean Ekins, Alexander Lepioshkin, Katarína Mikušová, Marta Esposito, University of Pavia, Russian Academy of Sciences [Moscow] (RAS), Microbiologie structurale - Structural Microbiology (Microb. Struc. (UMR_3528 / U-Pasteur_5)), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Ecole Polytechnique Fédérale de Lausanne (EPFL), University of Padova, Partenaires IRSTEA, Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA), Collaborative Drug Discovery, The Francis Crick Institute [London], Universidade Estadual Paulista Júlio de Mesquita Filho = São Paulo State University (UNESP), Comenius University in Bratislava, Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), The research leading to these results received funding mainly from the European Community's Seventh Framework Program (Grant 260872). Additional funding was from the Slovak Research and Development Agency (Contract No. DO7RP-0015-11), the Francis Crick Institute which receives core funding from Cancer Research UK, the UK Medical Research Council (MC_UP_A253_1111), and the Wellcome Trust. The CDD TB database was funded by the Bill and Melinda Gates Foundation (Grant no. 49852). L.B.M. receives partial support from the FAPESP (2011/21232-1), CNPq (140079/2013-0), and CAPES PDSE (99999.003125/2014-09) programs., European Project: 260872,EC:FP7:HEALTH,FP7-HEALTH-2010-single-stage,MM4TB(2011), Università degli Studi di Pavia = University of Pavia (UNIPV), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Università degli Studi di Padova = University of Padua (Unipd), and Università degli Studi di Firenze = University of Florence (UniFI)

Subjects
Models, Molecular, MESH: Mycobacterium tuberculosis, MESH: Carbon-Nitrogen Ligases, Protein Conformation, Mutant, Clinical Biochemistry, Antitubercular Agents, Drug Evaluation, Preclinical, MESH: Drug Design, Biochemistry, Activation, Metabolic, Mice, chemistry.chemical_compound, MESH: Protein Conformation, Drug Discovery, Carbon-Nitrogen Ligases, MESH: Animals, CTP synthetase, MESH: Bacterial Proteins, chemistry.chemical_classification, 0303 health sciences, MESH: Microbial Sensitivity Tests, biology, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Hep G2 Cells, General Medicine, MESH: Thiophenes, 3. Good health, Drug Discovery3003 Pharmaceutical Science, Molecular Biology, Molecular Medicine, Pharmacology, MESH: Drug Evaluation, Preclinical, Oxidoreductases, MESH: Models, Molecular, MESH: Activation, Metabolic, MESH: High-Throughput Screening Assays, Phenotypic screening, [PHYS.PHYS.PHYS-BIO-PH]Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph], Drug design, MESH: Hep G2 Cells, Microbial Sensitivity Tests, Thiophenes, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Article, Mycobacterium tuberculosis, 03 medical and health sciences, Bacterial Proteins, [CHIM.CRIS]Chemical Sciences/Cristallography, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Oxidoreductases, Gene, MESH: Mice, 030304 developmental biology, DNA ligase, MESH: Humans, 030306 microbiology, biology.organism_classification, MESH: Antitubercular Agents, High-Throughput Screening Assays, chemistry, Drug Design, biology.protein, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], DNA
Abstract

Summary To combat the emergence of drug-resistant strains of Mycobacterium tuberculosis, new antitubercular agents and novel drug targets are needed. Phenotypic screening of a library of 594 hit compounds uncovered two leads that were active against M. tuberculosis in its replicating, non-replicating, and intracellular states: compounds 7947882 (5-methyl-N-(4-nitrophenyl)thiophene-2-carboxamide) and 7904688 (3-phenyl-N-[(4-piperidin-1-ylphenyl)carbamothioyl]propanamide). Mutants resistant to both compounds harbored mutations in ethA (rv3854c), the gene encoding the monooxygenase EthA, and/or in pyrG (rv1699) coding for the CTP synthetase, PyrG. Biochemical investigations demonstrated that EthA is responsible for the activation of the compounds, and by mass spectrometry we identified the active metabolite of 7947882, which directly inhibits PyrG activity. Metabolomic studies revealed that pharmacological inhibition of PyrG strongly perturbs DNA and RNA biosynthesis, and other metabolic processes requiring nucleotides. Finally, the crystal structure of PyrG was solved, paving the way for rational drug design with this newly validated drug target., Graphical Abstract, Highlights • Two compounds activated by EthA kill M. tuberculosis through PyrG inhibition • EthA metabolite is active against PyrG and M. tuberculosis growth • Definition of the mechanism of activation and validation of PyrG as a new drug target, CTP synthetase PyrG, essential in Mycobacterium tuberculosis, could represent a new potential drug target. With a multidisciplinary approach, Mori et al. identify two compounds killing growing and dormant mycobacteria through PyrG inhibition, and define their mechanism of action.

Published
2015
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12. Design, synthesis and evaluation of new GEQ derivatives as inhibitors of InhA enzyme and Mycobacterium tuberculosis growth

Author

Giorgia Mori, Michel Baltas, Vania Bernardes-Génisson, Aurélien Chollet, Jana Korduláková, Frédéric Rodriguez, Jan Madacki, Isabelle Fabing, Maria Rosalia Pasca, Christian Lherbet, Annaïk Quémard, Patricia Constant, Christophe Menendez, Laboratoire de chimie de coordination (LCC), Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique (SPCMIB), Dipartimento di Biologia e Biotecnologie 'Lazzaro Spallanzani' = Department of Biology and Biotechnology [Univ di Pavia] (DBB UNIPV), Università degli Studi di Pavia = University of Pavia (UNIPV), Department of Biochemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Comenius University in Bratislava, Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Dipartimento di Biologia e Biotecnologie ‘Lazzaro Spallanzani’, University of Pavia, University of Pavia, Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées

Subjects
Models, Molecular, Indoles, Stereochemistry, efflux pumps, Medicinal chemistry, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, 01 natural sciences, Piperazines, Mycobacterium tuberculosis, 03 medical and health sciences, chemistry.chemical_compound, Structure-Activity Relationship, InhA, Bacterial Proteins, Amide, Drug Discovery, inhibitors, Moiety, Enzyme Inhibitors, 030304 developmental biology, Pharmacology, chemistry.chemical_classification, 0303 health sciences, biology, Dose-Response Relationship, Drug, Molecular Structure, 010405 organic chemistry, INHA, Organic Chemistry, General Medicine, biology.organism_classification, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, 3. Good health, 0104 chemical sciences, Anti-Bacterial Agents, Piperazine, Enzyme, chemistry, Docking (molecular), Drug Design, Efflux, Oxidoreductases
Abstract

A series of fluorene-based derivatives was synthesized and evaluated for inhibiting both InhA and Mycobacterium tuberculosis growth. These compounds were inspired by the previously reported Genz-10850 molecule, a good InhA inhibitor, but with a poor activity against M. tuberculosis growth. Structure activity relationships were performed by introducing the following chemical modifications: 1) the piperazine ring; 2) the amide group; 3) the aryl moiety; and 4) the fluorene moiety. Among these new derivatives, one of them was more effective against both the InhA activity and mycobacterial growth, compared to the hit compound. Docking studies were also performed to rationalize activities of these derivatives. Furthermore, we showed for the first time that efflux pump inhibitors potentiated the efficacy of Genz-10850 (GEQ) derivatives against M. tuberculosis growth, demonstrating that these compounds could be substrates of some efflux pumps. (C) 2015 Elsevier Masson SAS. All rights reserved.

Published
2015
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13. Pyridine-3,4-dicarboximide as starting material for the total synthesis of the natural product eupolauramine and its isomer iso-eupolauramine endowed with anti-tubercular activities

Author

Vania Bernardes-Génisson, Céline Deraeve, Giorgia Mori, Gildas Perdigão, Maria Rosalia Pasca, Geneviève Pratviel, Laboratoire de chimie de coordination (LCC), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Dipartimento di Biologia e Biotecnologie ‘Lazzaro Spallanzani’, University of Pavia, and University of Pavia

Subjects
Natural product, 010405 organic chemistry, Chemistry, Stereochemistry, Organic Chemistry, Total synthesis, 010402 general chemistry, 01 natural sciences, Biochemistry, Combinatorial chemistry, 0104 chemical sciences, 3. Good health, chemistry.chemical_compound, Yield (chemistry), Drug Discovery, Pyridine, Lactam, [CHIM.COOR]Chemical Sciences/Coordination chemistry, Anti tubercular, Eupolauramine
Abstract

A direct and convenient synthetic pathway for preparation of the key intermediate aza-isoindolinone 4a/4b, which could be ready obtained from pyridine-3,4-dicarboximide was described. This approach was valorized in the total synthesis of the natural product eupolauramine 7b and in the first synthesis of the position analog iso-eupolauramine 7a, which was obtained after 6 steps in an overall yield of 13%. The developed strategy represents the first synthetic approach employing a starting material already embedding the pyridine and the lactam cycles (cycles D and C, respectively) of the azaphenanthrene lactam framework. These compounds, mainly the new non-natural product, showed a good inhibitory activity against Mycobacterium tuberculosis growth. (C) 2015 Elsevier Ltd. All rights reserved.

Published
2015
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14. Synthesis of 3-heteryl substituted pyrrolidine-2,5-diones via catalytic Michael reaction and evaluation of their inhibitory activity against InhA and Mycobacterium tuberculosis

Author

Michel Baltas, Christian Lherbet, Frédéric Rodriguez, Giorgia Mori, Brigitte Guidetti, Zoia Voitenko, Maria Rosalia Pasca, Tetiana Matviiuk, Marian V. Gorichko, Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique (SPCMIB), Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Dipartimento di Biologia e Biotecnologie ‘Lazzaro Spallanzani’, University of Pavia, University of Pavia, Dipartimento di Biologia e Biotecnologie, Università degli Studi di Pavia, and Taras Shevchenko National University of Kyiv

Subjects
Models, Molecular, Pyrrolidines, Stereochemistry, Antitubercular Agents, Microbial Sensitivity Tests, Pyrrolidine, Catalysis, Mycobacterium tuberculosis, Structure-Activity Relationship, chemistry.chemical_compound, Bacterial Proteins, Succinimide, Drug Discovery, Humans, Tuberculosis, Structure–activity relationship, [CHIM]Chemical Sciences, ComputingMilieux_MISCELLANEOUS, Pharmacology, biology, Chemistry, INHA, Organic Chemistry, General Medicine, biology.organism_classification, 3. Good health, Mycobacterium tuberculosis H37Rv, Michael reaction, Oxidoreductases
Abstract

In the present paper, we report the synthesis via catalytic Michael reaction and biological results of a series of 3-heteryl substituted pyrrolidine-2,5-dione derivatives as moderate inhibitors against Mycobacterium tuberculosis H37Rv growth. Some of them present also inhibition activities against InhA.

Published
2014
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15. Analogous mechanisms of resistance to benzothiazinones and dinitrobenzamides in Mycobacterium smegmatis

Author

Priscille Brodin, Menico Rizzi, Silvia Buroni, Giovanna Riccardi, Maria Loreto Incandela, Giovanna Valentini, Maria Rosalia Pasca, Laurent R. Chiarelli, Giulia Degiacomi, Monica Contreras-Dominguez, Fanny Anne Ewann, Sung-Jun Han, Giorgia Mori, Jaeseung Kim, Ana Luisa de Jesus Lopes Ribeiro, and Youngsam Park

Subjects
Bacterial Diseases, Extensively Drug-Resistant Tuberculosis, Mutant, Thiazines, medicine.disease_cause, 01 natural sciences, Biochemistry, Nitroreductase, chemistry.chemical_compound, Catalytic Domain, Tuberculosis, Multidrug-Resistant, Drug Discovery, chemistry.chemical_classification, 0303 health sciences, Mutation, Multidisciplinary, Mycobacterium smegmatis, Multi-Drug-Resistant Tuberculosis, 3. Good health, Anti-Bacterial Agents, Dinitrobenzenes, Infectious Diseases, Benzamides, Medicine, Public Health, Research Article, Biotechnology, Drugs and Devices, Drug Research and Development, Science, Blotting, Western, Racemases and Epimerases, Mycobacterium Infections, Nontuberculous, Biology, Real-Time Polymerase Chain Reaction, Microbiology, Mycobacterium, Mycobacterium tuberculosis, 03 medical and health sciences, Biosynthesis, medicine, Tuberculosis, RNA, Messenger, Gene, 030304 developmental biology, 010405 organic chemistry, Tropical Diseases (Non-Neglected), Bacteriology, Nitroreductases, biology.organism_classification, Molecular biology, 0104 chemical sciences, Enzyme, chemistry, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Chromatography, Liquid
Abstract

Tuberculosis is still a leading cause of death worldwide. The selection and spread of Mycobacterium tuberculosis multidrug-resistant (MDR-TB) and extensively drug-resistant strains (XDR-TB) is a severe public health problem. Recently, two different classes of chemical series, the benzothiazinones (BTZ) and the dinitrobenzamide (DNB) derivatives have been found to be highly active against M. tuberculosis, including XDR-TB strains. The target of BTZs is DprE1 protein which works in concert with DprE2 to form the heteromeric decaprenylphosphoryl-β-D-ribose 2′-epimerase, involved in Decaprenyl-Phospho-Arabinose (DPA) biosynthesis. Interestingly, it has been shown that the DNBs block the same pathway thus suggesting that both drugs could share the same target. Moreover, in Mycobacterium smegmatis the overexpression of the NfnB nitroreductase led to the inactivation of the BTZs by reduction of a critical nitro-group to an amino-group. In this work several spontaneous M. smegmatis mutants resistant to DNBs were isolated. Sixteen mutants, showing high levels of DNB resistance, exhibited a mutation in the Cys394 of DprE1. Using fluorescence titration and mass spectrometry it has been possible to monitor the binding between DprE1 and DNBs, achieving direct evidence that MSMEG_6382 is the cellular target of DNBs in mycobacteria. Additionally, M. smegmatis mutants having low levels of resistance to DNBs harbor various mutations in MSMEG_6503 gene encoding the transcriptional repressor of the nitroreductase NfnB. By LC/MS2 analysis it has been demonstrated that NfnB is responsible for DNB inactivation. Taken together, our data demonstrate that both DNB and BTZ drugs share common resistance mechanisms in M. smegmatis.

Published
2011

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