Antisense Inhibitors Retain Activity in Pulmonary Models of Burkholderia Infection

Seth M. Daly, Carolyn R. Sturge, Kimberly R. Marshall-Batty, Christina F. Felder-Scott, Raksha Jain, Bruce L. Geller, David E. Greenberg

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

The Burkholderia cepacia complex is a group of Gram-negative bacteria that are opportunistic pathogens in immunocompromised individuals, such as those with cystic fibrosis (CF) or chronic granulomatous disease (CGD). Burkholderia are intrinsically resistant to many antibiotics and the lack of antibiotic development necessitates novel therapeutics. Peptide-conjugated phosphorodiamidate morpholino oligomers are antisense molecules that inhibit bacterial mRNA translation. Targeting of PPMOs to the gene acpP, which is essential for membrane synthesis, lead to defects in the membrane and ultimately bactericidal activity. Exploration of additional PPMO sequences identified the ATG and Shine-Dalgarno sites as the most efficacious for targeting acpP. The CF lung is a complex microenvironment, but PPMO inhibition was still efficacious in an artificial model of CF sputum. PPMOs had low toxicity in human CF cells at doses that were antibacterial. PPMOs also reduced the bacterial burden in the lungs of immunocompromised CyBB mice, a model of CGD. Finally, the use of multiple PPMOs was efficacious in inhibiting the growth of both Burkholderia and Pseudomonas in an in vitro model of coinfection. Due to the intrinsic resistance of Burkholderia to traditional antibiotics, PPMOs represent a novel and viable approach to the treatment of Burkholderia infections.

Original languageEnglish (US)
Pages (from-to)806-814
Number of pages9
JournalACS Infectious Diseases
Volume4
Issue number5
DOIs
StatePublished - May 11 2018

Keywords

  • antisense
  • artificial sputum
  • Burkholaderia cepacia complex (Bcc)
  • peptide-conjugated phosphorodiamidate morpholino oligomers (PPMO)
  • pneumonia

ASJC Scopus subject areas

  • Infectious Diseases

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