title: β-Lactamase inhibition by avibactam in Mycobacterium abscessus.
abstract: OBJECTIVE
  Two β-lactams, cefoxitin and imipenem, are part of the reference treatment for pulmonary infections with Mycobacterium abscessus. M. abscessus has recently been shown to produce a broad-spectrum β-lactamase, BlaMab, indicating that the combination of β-lactams with a BlaMab inhibitor may improve treatment efficacy. The objectives of this study were to evaluate the impact of BlaMab production on the efficacy of β-lactams in vitro and to assess the benefit of BlaMab inhibition on the activity of β-lactams intracellularly and in an animal model.
  
  
  METHODS
  We analysed the mechanism and kinetics of BlaMab inactivation by avibactam, a non-β-lactam β-lactamase inhibitor currently in Phase III of development, in combination with ceftazidime for the treatment of serious infections due to Gram-negative bacteria. We then deleted the gene encoding BlaMab to assess the extent of BlaMab inhibition by avibactam based on a comparison of the impact of chemical and genetic inactivation. Finally, the efficacy of amoxicillin in combination with avibactam was evaluated in cultured human macrophages and in a zebrafish model of M. abscessus infection.
  
  
  RESULTS
  We showed that avibactam efficiently inactivated BlaMab via the reversible formation of a covalent adduct. An inhibition of BlaMab by avibactam was observed in both infected macrophages and zebrafish.
  
  
  CONCLUSIONS
  Our data identify avibactam as the first efficient inhibitor of BlaMab and strongly suggest that β-lactamase inhibition should be evaluated to provide improved therapeutic options for M. abscessus infections.
authors.affiliation: INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006, Paris, France Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006 Paris, France Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006 Paris, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Dubée
authors.affiliation: Laboratoire de Dynamique des Interactions Membranaires Normales et Pathologiques, Université de Montpellier 2 et 1, CNRS, UMR 5235, Montpellier, France INSERM, DIMNP, Montpellier, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Bernut
authors.affiliation: INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006, Paris, France Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006 Paris, France Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006 Paris, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Cortes
authors.affiliation: Laboratoire de Dynamique des Interactions Membranaires Normales et Pathologiques, Université de Montpellier 2 et 1, CNRS, UMR 5235, Montpellier, France INSERM, DIMNP, Montpellier, France.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Lesne
authors.affiliation: INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006, Paris, France Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006 Paris, France Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006 Paris, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Dorchene
authors.affiliation: INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006, Paris, France Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006 Paris, France Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006 Paris, France.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Lefebvre
authors.affiliation: INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006, Paris, France Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006 Paris, France Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006 Paris, France.
authors.forename: Jean-Emmanuel
authors.initials: JE
authors.lastname: Hugonnet
authors.affiliation: INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006, Paris, France Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006 Paris, France Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006 Paris, France Assistance Publique-Hôpitaux de Paris, Service de Microbiologie, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Gutmann
authors.affiliation: INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006, Paris, France Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006 Paris, France Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006 Paris, France Assistance Publique-Hôpitaux de Paris, Service de Microbiologie, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Mainardi
authors.affiliation: EA3647 - EPIM, Université de Versailles St-Quentin-en-Yvelines et UFR des Sciences de la Santé, Montigny-le-Bretonneux, France Assistance Publique - Hôpitaux de Paris (AP-HP), Service de Microbiologie, Hôpital Raymond Poincaré, Garches, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Herrmann
authors.affiliation: EA3647 - EPIM, Université de Versailles St-Quentin-en-Yvelines et UFR des Sciences de la Santé, Montigny-le-Bretonneux, France Assistance Publique - Hôpitaux de Paris (AP-HP), Service de Microbiologie, Hôpital Raymond Poincaré, Garches, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Gaillard
authors.affiliation: Laboratoire de Dynamique des Interactions Membranaires Normales et Pathologiques, Université de Montpellier 2 et 1, CNRS, UMR 5235, Montpellier, France INSERM, DIMNP, Montpellier, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Kremer
authors.affiliation: INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006, Paris, France Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006 Paris, France Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006 Paris, France michel.arthur@crc.jussieu.fr.
authors.forename: Michel
authors.initials: M
authors.lastname: Arthur
mesh_terms: D000658:Amoxicillin / Q000378:metabolism / Q000627:therapeutic use; D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000627:therapeutic use; D053961:Azabicyclo Compounds / Q000378:metabolism* / Q000627:therapeutic use*; D002460:Cell Line; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology; D023421:Models, Animal; D009161:Mycobacterium / Q000187:drug effects* / Q000201:enzymology*; D009164:Mycobacterium Infections / Q000188:drug therapy / Q000382:microbiology; D016896:Treatment Outcome; D015027:Zebrafish; D065093:beta-Lactamase Inhibitors / Q000378:metabolism* / Q000627:therapeutic use*; D001618:beta-Lactamases / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D053961:Azabicyclo Compounds; D065093:beta-Lactamase Inhibitors; C543519:avibactam; D000658:Amoxicillin; D001618:beta-Lactamases
keywords: M. abscessus; cystic fibrosis; non-tuberculous mycobacteria; therapy; β-lactams