Erin K Sully1, Bruce L Geller1, Lixin Li1, Christina M Moody1, Stacey M Bailey2, Amy L Moore2, Michael Wong2,3, Patrice Nordmann4, Seth M Daly5, Carolyn R Sturge5, David E Greenberg5,6. 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.
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.
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