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1. A new piperidinol derivative targeting mycolic acid transport in Mycobacterium abscessus

Author

Christian, Dupont, Albertus, Viljoen, Faustine, Dubar, Mickaël, Blaise, Audrey, Bernut, Alexandre, Pawlik, Christiane, Bouchier, Roland, Brosch, Yann, Guérardel, Joël, Lelièvre, Lluis, Ballell, Jean-Louis, Herrmann, Christophe, Biot, Laurent, Kremer, Infection et inflammation (2I), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Centre d’études d’Agents Pathogènes et Biotechologies pour la Santé (CPBS), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Institut National de la Recherche Agronomique (INRA)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Pathogénomique mycobactérienne intégrée - Integrated Mycobacterial Pathogenomics, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Génopole, Institut Pasteur [Paris], GlaxoSmithKline, Glaxo Smith Kline, This study was supported by the French National Research Agency (http://www.agence-nationale-recherche.fr/) (DIMYVIR ANR‐13‐BSV3‐0007‐01). We wish also to thank the Association Gregory Lemarchal and Vaincre La Mucoviscidose (RF20130500835) for funding CD and the InfectioPôle Sud for funding AV. LK and RB acknowledge the support by the Fondation pour la Recherche Médicale (FRM) (DEQ20150331719 and DEQ20130326471). This study was funded by grant from the Université de Lille1 (Bonus Qualité Recherche) to FD., ANR-13-BSV3-0007,DIMYVIR,Identification et Visualisation des Mécanismes Permettant l'Acquisition d'un Phénotype Invasif chez les Mycobactéries Pathogènes à Croissance Rapide(2013), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), Infection et inflammation chronique (2I), Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), and Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)

Subjects
Binding Sites, [SDV]Life Sciences [q-bio], Antitubercular Agents, Mycobacterium Infections, Nontuberculous, Nontuberculous Mycobacteria, MESH: Mycolic Acids, MESH: Mycobacterium Infections, Nontuberculous, MESH: Antitubercular Agents, Disease Models, Animal, MESH: Piperidines, Mycolic Acids, Piperidines, MESH: Binding Sites, MESH: Nontuberculous Mycobacteria, Animals, MESH: Animals, MESH: Disease Models, Animal, MESH: Zebrafish, Zebrafish
Abstract

International audience; The natural resistance of Mycobacterium abscessus to most commonly available antibiotics seriously limits chemotherapeutic treatment options, which is particularly challenging for cystic fibrosis patients infected with this rapid-growing mycobacterium. New drugs with novel molecular targets are urgently needed against this emerging pathogen. However, the discovery of such new chemotypes has not been appropriately performed. Here, we demonstrate the utility of a phenotypic screen for bactericidal compounds against M. abscessus using a library of compounds previously validated for activity against M. tuberculosis. We identified a new piperidinol-based molecule, PIPD1, exhibiting potent activity against clinical M. abscessus strains in vitro and in infected macrophages. Treatment of infected zebrafish with PIPD1 correlated with increased embryo survival and decreased bacterial burden. Whole genome analysis of M. abscessus strains resistant to PIPD1 identified several mutations in MAB_4508, encoding a protein homologous to MmpL3. Biochemical analyses demonstrated that while de novo mycolic acid synthesis was unaffected, PIPD1 strongly inhibited the transport of trehalose monomycolate, thereby abrogating mycolylation of arabinogalactan. Mapping the mutations conferring resistance to PIPD1 on a MAB_4508 tridimensional homology model defined a potential PIPD1-binding pocket. Our data emphasize a yet unexploited chemical structure class against M. abscessus infections with promising translational development possibilities.

Published
2016
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2. Hydrolysis of clavulanate by Mycobacterium tuberculosis β-lactamase BlaC harboring a canonical SDN motif

Author

David Barros, Daria Soroka, Sébastien Triboulet, Michel Arthur, Lluis Ballell, Jean-Emmanuel Hugonnet, Jean-Luc Mainardi, Herman van Tilbeurgh, Fabrice Compain, Vincent Dubée, Inès Li de la Sierra-Gallay, Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Fonction et Architecture des Assemblages Macromoléculaires (FAAM), Département Biochimie, Biophysique et Biologie Structurale (B3S), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut de biochimie et biophysique moléculaire et cellulaire (IBBMC), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Diseases of the Developing World [Tres Cantos, Madrid] (DDW), Tres Cantos Open Lab Foundation [London, UK] (TCOLF)-GlaxoSmithKline [Headquarters, London, UK] (GSK), ANR-10-INBS-0005,FRISBI,Infrastructure Française pour la Biologie Structurale Intégrée(2010), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Diseases of the Developing World, GlaxoSmithKline, Madrid, ANR-10-INBS-05-01/10-INBS-0005,FRISBI,Infrastructure Française pour la Biologie Structurale Intégrée(2010), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers ( CRC ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ), Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Sud - Paris 11 ( UP11 ), Fonction et Architecture des Assemblages Macromoléculaires ( FAAM ), Département Biochimie, Biophysique et Biologie Structurale ( B3S ), Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Sud - Paris 11 ( UP11 ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Sud - Paris 11 ( UP11 ) -Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Sud - Paris 11 ( UP11 ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Sud - Paris 11 ( UP11 ), Institut de biochimie et biophysique moléculaire et cellulaire ( IBBMC ), Université Paris-Sud - Paris 11 ( UP11 ) -Centre National de la Recherche Scientifique ( CNRS ), ANR-10-INSB-05-01,FRISBI,French Infrastructure for Integrated Structural Biology, Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Institut de Biologie Intégrative de la Cellule ( I2BC ), and Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS )

Subjects
Decarboxylation, [SDV]Life Sciences [q-bio], Microbial Sensitivity Tests, Biology, Mycobacterium abscessus, beta-Lactams, beta-Lactam Resistance, beta-Lactamases, Microbiology, Acylation, Mycobacterium tuberculosis, 03 medical and health sciences, chemistry.chemical_compound, Hydrolysis, Mechanisms of Resistance, Clavulanic acid, Hydrolase, medicine, Pharmacology (medical), Clavulanic Acid, 030304 developmental biology, Pharmacology, 0303 health sciences, [ SDV ] Life Sciences [q-bio], 030306 microbiology, Faropenem, biology.organism_classification, 3. Good health, Infectious Diseases, Biochemistry, chemistry, medicine.drug
Abstract

Combinations of β-lactams with clavulanate are currently being investigated for tuberculosis treatment. Since Mycobacterium tuberculosis produces a broad spectrum β-lactamase, BlaC, the success of this approach could be compromised by the emergence of clavulanate-resistant variants, as observed for inhibitor-resistant TEM variants in enterobacteria. Previous analyses based on site-directed mutagenesis of BlaC have led to the conclusion that this risk was limited. Here, we used a different approach based on determination of the crystal structure of β-lactamase Bla MAb of Mycobacterium abscessus , which efficiently hydrolyzes clavulanate. Comparison of Bla MAb and BlaC allowed for structure-assisted site-directed mutagenesis of BlaC and identification of the G 132 N substitution that was sufficient to switch the interaction of BlaC with clavulanate from irreversible inactivation to efficient hydrolysis. The substitution, which restored the canonical SDN motif (SDG→SDN), allowed for efficient hydrolysis of clavulanate, with a more than 10 4 -fold increase in k cat (0.41 s −1 ), without affecting the hydrolysis of other β-lactams. Mass spectrometry revealed that acylation of BlaC and of its G 132 N variant by clavulanate follows similar paths, involving sequential formation of two acylenzymes. Decarboxylation of the first acylenzyme results in a stable secondary acylenzyme in BlaC, whereas hydrolysis occurs in the G 132 N variant. The SDN/SDG polymorphism defines two mycobacterial lineages comprising rapidly and slowly growing species, respectively. Together, these results suggest that the efficacy of β-lactam–clavulanate combinations may be limited by the emergence of resistance. β-Lactams active without clavulanate, such as faropenem, should be prioritized for the development of new therapies.

Published
2015
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3. Improved BM212 MmpL3 inhibitor analogue shows efficacy in acute murine model of tuberculosis infection

Author

Fabrizio Manetti, Maria Rosalia Pasca, Fátima Ortega, Alessandro De Logu, Joaquín Rullas, Mariangela Biava, E Agus, Lluis Ballell, Robert H. Bates, Scott G. Franzblau, Edda De Rossi, Maurizio Botta, Baojie Wae, Martina Cocozza, Giulio Cesare Porretta, Giovanna Poce, Valentina La Rosa, S. Alfonso, Department of Medicinal Chemistry and Technologies, Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Diseases of the Developing World [Tres Cantos, Madrid] (DDW), Tres Cantos Open Lab Foundation [London, UK] (TCOLF)-GlaxoSmithKline [Headquarters, London, UK] (GSK), Dipartimento di Scienze della Vita e dell'Ambiente, Università di Cagliari, Dipartimento di Biologia e Biotecnologie, Università degli Studi di Pavia, Institute for Tuberculosis Research, University of Illinois [Chicago] (UIC), University of Illinois System-University of Illinois System, Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Istituto Pasteur Fondazione Cenci-Bolognetti (Italy), MIUR-PRIN 2008 (Italy), MIUR 2011 (Progetti di Ricerca di Ateneo)(Italy) and Tres Cantos Open Lab Foundation, European Project: 261378,EC:FP7:HEALTH,FP7-HEALTH-2010-single-stage,ORCHID(2011), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Università degli Studi di Cagliari = University of Cagliari (UniCa), Università degli Studi di Pavia = University of Pavia (UNIPV), and Università degli Studi di Siena = University of Siena (UNISI)

Subjects
MESH: Mycobacterium tuberculosis, Mouse, Druggability, MESH: Piperazines, lcsh:Medicine, Pharmacology, Piperazines, chemistry.chemical_compound, Mice, Drug Discovery, MESH: Animals, MESH: Tuberculosis, lcsh:Science, MESH: Bacterial Proteins, MESH: Antibiotics, Antitubercular, Drug Distribution, 0303 health sciences, MESH: Microbial Sensitivity Tests, Multidisciplinary, biology, Drug discovery, Isoniazid, Animal Models, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, 3. Good health, Chemistry, Thiomorpholine, Infectious Diseases, Lipophilicity, MESH: Pyrroles, Medicine, Female, medicine.drug, Research Article, Drugs and Devices, Drug Research and Development, Microbial Sensitivity Tests, Drug Absorption, Cell Line, Mycobacterium tuberculosis, MESH: Microsomes, 03 medical and health sciences, Model Organisms, Bacterial Proteins, In vivo, Genetic Mutation, Microsomes, medicine, Genetics, Animals, Humans, Tuberculosis, Pyrroles, Pharmacokinetics, Antibiotics, Antitubercular, Biology, MESH: Mice, 030304 developmental biology, MESH: Humans, 030306 microbiology, lcsh:R, Tropical Diseases (Non-Neglected), biology.organism_classification, In vitro, MESH: Cell Line, chemistry, lcsh:Q, Medicinal Chemistry, MESH: Female
Abstract

International audience; 1,5-Diphenyl pyrroles were previously identified as a class of compounds endowed with high in vitro efficacy against M. tuberculosis. To improve the physical chemical properties and drug-like parameters of this class of compounds, a medicinal chemistry effort was undertaken. By selecting the optimal substitution patterns for the phenyl rings at N1 and C5 and by replacing the thiomorpholine moiety with a morpholine one, a new series of compounds was produced. The replacement of the sulfur with oxygen gave compounds with lower lipophilicity and improved in vitro microsomal stability. Moreover, since the parent compound of this family has been shown to target MmpL3, mycobacterial mutants resistant to two compounds have been isolated and characterized by sequencing the mmpL3 gene; all the mutants showed point mutations in this gene. The best compound identified to date was progressed to dose-response studies in an acute murine TB infection model. The resulting ED(99) of 49 mg/Kg is within the range of commonly employed tuberculosis drugs, demonstrating the potential of this chemical series. The in vitro and in vivo target validation evidence presented here adds further weight to MmpL3 as a druggable target of interest for anti-tubercular drug discovery.

Published
2013
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