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J Antimicrob Chemother. 2015 Apr;70(4):1051-8. doi: 10.1093/jac/dku510. Epub 2014 Dec 18.

β-Lactamase inhibition by avibactam in Mycobacterium abscessus.

Author information

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.

KEYWORDS:

M. abscessus; cystic fibrosis; non-tuberculous mycobacteria; therapy; β-lactams

PMID:
25525201
DOI:
10.1093/jac/dku510
[Indexed for MEDLINE]

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