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

Sully, Erin K.; Geller, Bruce L.; Li, Lixin; Moody, Christina M.; Bailey, Stacey M.; Moore, Amy L.; Wong, Michael; Nordmann, Patrice; Daly, Seth M.; Sturge, Carolyn R.; Greenberg, David E.

doi:10.1093/jac/dkw476

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Journal article

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

Sully, Erin K. Department of Microbiology, Oregon State University, Corvallis, USA
Geller, Bruce L. Department of Microbiology, Oregon State University, Corvallis, USA
Li, Lixin Department of Microbiology, Oregon State University, Corvallis, USA
Moody, Christina M. Department of Microbiology, Oregon State University, Corvallis, USA
Bailey, Stacey M. Sarepta Therapeutics, Cambridge, MA, USA
Moore, Amy L. Sarepta Therapeutics, Cambridge, MA, USA
Wong, Michael Sarepta Therapeutics, Cambridge, MA, USA
Nordmann, Patrice Medical and Molecular Microbiology Unit, Department of Medicine, Faculty of Science, University of Fribourg, Switzerland
Daly, Seth M. Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, USA
Sturge, Carolyn R. Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, USA
Greenberg, David E. Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, USA - Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, USA

01.03.2017

Published in:

Journal of Antimicrobial Chemotherapy. - 2017, vol. 72, no. 3, p. 782–790

English 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.

Faculty

Faculté des sciences et de médecine

Department

Médecine 3ème année

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