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J Antimicrob Chemother. 2018 Feb 1;73(2):425-430. doi: 10.1093/jac/dkx403.

Bacterial zincophore [S,S]-ethylenediamine-N,N'-disuccinic acid is an effective inhibitor of MBLs.

Author information

1
Institute of Pharmaceutical Chemistry, Goethe-University, Max-von-Laue Str. 9, D-60439, Frankfurt, Germany.
2
Institute of Medical Microbiology and Infection Control, Hospital of Goethe-University, Paul-Ehrlich-Str. 40, D-60596, Frankfurt, Germany.

Abstract

Objectives:

Carbapenemases such as MBLs are spreading among Gram-negative bacterial pathogens. Infections due to these MDR bacteria constitute a major global health challenge. Therapeutic strategies against carbapenemase-producing bacteria include β-lactamase inhibitor combinations. [S,S]-ethylenediamine-N,N'-disuccinic acid (EDDS) is a chelator and potential inhibitor of MBLs. We investigated the activity of EDDS in combination with imipenem against MBL-producing bacteria in vitro as well as in vivo.

Methods:

The inhibitory activity of EDDS was analysed by means of a fluorescence-based assay using purified recombinant MBLs, i.e. NDM-1, VIM-1, SIM-1 and IMP-1. The in vitro activity of imipenem ± EDDS against mutants as well as clinical isolates expressing MBLs was evaluated by broth microdilution assay. The in vivo activity of imipenem ± EDDS was analysed in a Galleria mellonella infection model.

Results:

EDDS revealed potent MBL inhibitory activity against purified NDM-1, weaker activity against VIM-1 and SIM-1, and marginal activity against IMP-1. EDDS did not exhibit any intrinsic antibacterial activity, but enabled a concentration-dependent potentiation of imipenem against mutants as well as clinical isolates expressing various MBLs. The in vivo model showed a significantly better survival rate for imipenem + EDDS-treated G. mellonella larvae infected with NDM-1-producing Klebsiella pneumoniae compared with monotherapy with imipenem.

Conclusions:

The bacterial natural zincophore EDDS is a potent MBL inhibitor and in combination with imipenem overcomes MBL-mediated carbapenem resistance in vitro and in vivo.

PMID:
29186432
DOI:
10.1093/jac/dkx403

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