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J Antimicrob Chemother. 2017 Mar 1;72(3):782-790. doi: 10.1093/jac/dkw476.

Peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO) restores carbapenem susceptibility to NDM-1-positive pathogens in vitro and in vivo.

Author information

1
Department of Microbiology, Oregon State University, Corvallis, OR, USA.
2
Sarepta Therapeutics, Cambridge, MA, USA.
3
Division of Infectious Diseases, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA, USA.
4
Medical and Molecular Microbiology Unit, Department of Medicine, Faculty of Science, University of Fribourg, Fribourg, Switzerland.
5
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
6
Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Abstract

Objectives:

The objective of this study was to test the efficacy of an inhibitor of the New Delhi metallo-β- lactamase (NDM-1). Inhibiting expression of this type of antibiotic-resistance gene has the potential to restore antibiotic susceptibility in all bacteria carrying the gene.

Methods:

We have constructed a peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO) that selectively inhibits the expression of NDM-1 and examined its ability to restore susceptibility to meropenem in vitro and in vivo .

Results:

In vitro , the PPMO reduced the MIC of meropenem for three different genera of pathogens that express NDM-1. In a murine model of lethal E. coli sepsis, the PPMO improved survival (92%) and reduced systemic bacterial burden when given concomitantly with meropenem.

Conclusions:

These data show that a PPMO can restore antibiotic susceptibility in vitro and in vivo and that the combination of PPMO and meropenem may have therapeutic potential against certain class B carbapenem-resistant infections in multiple genera of Gram-negative pathogens.

PMID:
27999041
PMCID:
PMC5890718
DOI:
10.1093/jac/dkw476
[Indexed for MEDLINE]
Free PMC Article

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