title: Peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO) restores carbapenem susceptibility to NDM-1-positive pathogens in vitro and in vivo.
abstract: 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.
  
  
  
  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 .
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Microbiology, Oregon State University, Corvallis, OR, USA.
authors.forename: Erin K
authors.initials: EK
authors.lastname: Sully
authors.affiliation: Department of Microbiology, Oregon State University, Corvallis, OR, USA.
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Geller
authors.affiliation: Department of Microbiology, Oregon State University, Corvallis, OR, USA.
authors.forename: Lixin
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Microbiology, Oregon State University, Corvallis, OR, USA.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Moody
authors.affiliation: Sarepta Therapeutics, Cambridge, MA, USA.
authors.forename: Stacey M
authors.initials: SM
authors.lastname: Bailey
authors.affiliation: Sarepta Therapeutics, Cambridge, MA, USA.
authors.forename: Amy L
authors.initials: AL
authors.lastname: Moore
authors.affiliation: Sarepta Therapeutics, Cambridge, MA, USA.|Division of Infectious Diseases, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Wong
authors.affiliation: Medical and Molecular Microbiology Unit, Department of Medicine, Faculty of Science, University of Fribourg, Fribourg, Switzerland.
authors.forename: Patrice
authors.initials: P
authors.lastname: Nordmann
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Seth M
authors.initials: SM
authors.lastname: Daly
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Carolyn R
authors.initials: CR
authors.lastname: Sturge
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.|Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Greenberg
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D058491:Bacterial Load / Q000187:drug effects*; D024901:Drug Resistance, Multiple, Bacterial; D004359:Drug Therapy, Combination; D004755:Enterobacteriaceae / Q000187:drug effects* / Q000201:enzymology; D004756:Enterobacteriaceae Infections / Q000188:drug therapy / Q000382:microbiology; D004926:Escherichia coli / Q000187:drug effects; D000077731:Meropenem; D051379:Mice; D008826:Microbial Sensitivity Tests; D060172:Morpholinos / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D018805:Sepsis / Q000188:drug therapy / Q000382:microbiology; D013845:Thienamycins / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D001618:beta-Lactamases / Q000235:genetics* / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D060172:Morpholinos; D013845:Thienamycins; D001618:beta-Lactamases; C552864:beta-lactamase NDM-1; D000077731:Meropenem