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

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

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)782-790
Number of pages9
JournalJournal of Antimicrobial Chemotherapy
Volume72
Issue number3
DOIs
StatePublished - Mar 1 2017

ASJC Scopus subject areas

  • Pharmacology
  • Microbiology (medical)
  • Infectious Diseases
  • Pharmacology (medical)

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