Vincent Dubée1, Audrey Bernut2, Mélanie Cortes1, Tiffany Lesne2, Delphine Dorchene1, Anne-Laure Lefebvre1, Jean-Emmanuel Hugonnet1, Laurent Gutmann3, Jean-Luc Mainardi3, Jean-Louis Herrmann4, Jean-Louis Gaillard4, Laurent Kremer2, Michel Arthur5. 1. 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. 2. Laboratoire de Dynamique des Interactions Membranaires Normales et Pathologiques, Université de Montpellier 2 et 1, CNRS, UMR 5235, Montpellier, France INSERM, DIMNP, Montpellier, France. 3. 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. 4. 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. 5. 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.
Abstract
OBJECTIVES: 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.
OBJECTIVES: 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: Rose C Lopeman; James Harrison; Daniel L Rathbone; Maya Desai; Peter A Lambert; Jonathan A G Cox Journal: Sci Rep Date: 2020-01-27 Impact factor: 4.379
Authors: Amit Kaushik; Nicole C Ammerman; Nicole M Parrish; Eric L Nuermberger Journal: Antimicrob Agents Chemother Date: 2019-08-23 Impact factor: 5.191