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Antisense Inhibitors Retain Activity in Pulmonary Models of Burkholderia Infection

  1. Author:
    Daly, Seth M.
    Sturge, Carolyn R.
    Batty, Kimberly
    Felder-Scott, Christina F.
    Jain, Raksha
    Geller, Bruce L.
    Greenberg, David E.
  2. Author Address

    UT Southwestern, Dept Internal Med, 5323 Harry Hines Blvd, Dallas, TX 75390 USA.UT Southwestern, Dept Microbiol, 5323 Harry Hines Blvd, Dallas, TX 75390 USA.Oregon State Univ, Dept Microbiol, 226 Nash Hall, Corvallis, OR 97331 USA.Univ New Mexico, Coll Pharm, Dept Pharmaceut Sci, Albuquerque, NM 87131 USA.Frederick Natl Lab Canc Res, Leidos Biomed Res Inc, Appl Dev Res Directorate, Neutrophil Monitoring Lab, Frederick, MD 21702 USA.
    1. Year: 2018
    2. Date: May
  1. Journal: ACS INFECTIOUS DISEASES
  2. AMER CHEMICAL SOC,
    1. 4
    2. 5
    3. Pages: 806-814
  3. Type of Article: Article
  4. ISSN: 2373-8227
  1. 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.

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External Sources

  1. DOI: 10.1021/acsinfecdis.7b0023
  2. PMID: 29461800
  3. WOS: 000432478400016

Library Notes

  1. Fiscal Year: FY2017-2018
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