1. Academic Validation
  2. Inhibition of Pseudomonas aeruginosa by Peptide-Conjugated Phosphorodiamidate Morpholino Oligomers

Inhibition of Pseudomonas aeruginosa by Peptide-Conjugated Phosphorodiamidate Morpholino Oligomers

  • Antimicrob Agents Chemother. 2017 Mar 24;61(4):e01938-16. doi: 10.1128/AAC.01938-16.
James J Howard 1 Carolyn R Sturge 1 Dina A Moustafa 2 Seth M Daly 1 Kimberly R Marshall-Batty 1 Christina F Felder 1 Danniel Zamora 1 Marium Yabe-Gill 1 Maria Labandeira-Rey 1 Stacey M Bailey 3 Michael Wong 3 4 Joanna B Goldberg 2 Bruce L Geller 5 David E Greenberg 6 7
Affiliations

Affiliations

  • 1 Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
  • 2 Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA.
  • 3 Sarepta Therapeutics, Cambridge, Massachusetts, USA.
  • 4 Harvard Medical School, Boston, Massachusetts, USA.
  • 5 Department of Microbiology, Oregon State University, Corvallis, Oregon, USA.
  • 6 Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA david.greenberg@utsouthwestern.edu.
  • 7 Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Abstract

Pseudomonas aeruginosa is a highly virulent, multidrug-resistant pathogen that causes significant morbidity and mortality in hospitalized patients and is particularly devastating in patients with cystic fibrosis. Increasing Antibiotic resistance coupled with decreasing numbers of Antibiotics in the developmental pipeline demands novel Antibacterial approaches. Here, we tested peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs), which inhibit translation of complementary mRNA from specific, essential genes in P. aeruginosa PPMOs targeted to acpP, lpxC, and rpsJ, inhibited P. aeruginosa growth in many clinical strains and activity of PPMOs could be enhanced 2- to 8-fold by the addition of polymyxin B nonapeptide at subinhibitory concentrations. The PPMO targeting acpP was also effective at preventing P. aeruginosa PAO1 biofilm formation and at reducing existing biofilms. Importantly, treatment with various combinations of a PPMO and a traditional Antibiotic demonstrated synergistic growth inhibition, the most effective of which was the PPMO targeting rpsJ with tobramycin. Furthermore, treatment of P. aeruginosa PA103-infected mice with PPMOs targeting acpP, lpxC, or rpsJ significantly reduced the Bacterial burden in the lungs at 24 h by almost 3 logs. Altogether, this study demonstrates that PPMOs targeting the essential genes acpP, lpxC, or rpsJ in P. aeruginosa are highly effective at inhibiting growth in vitro and in vivo These data suggest that PPMOs alone or in combination with Antibiotics represent a novel approach to addressing the problems associated with rapidly increasing Antibiotic resistance in P. aeruginosa.

Keywords

PPMO; Pseudomonas aeruginosa; antibiotic resistance; antimicrobial agents; antisense; experimental therapeutics; phosphorodiamidate morpholino oligomer.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-P10559
    Cell-Penetrating Peptide