Antisense Inhibitors Retain Activity in Pulmonary Models of Burkholderia Infection.
Seth M DalyCarolyn R SturgeKimberly R Marshall-BattyChristina F Felder-ScottRaksha JainBruce L GellerDavid E GreenbergPublished in: ACS infectious diseases (2018)
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.
Keyphrases
- cystic fibrosis
- endothelial cells
- stem cells
- cancer therapy
- small molecule
- pulmonary hypertension
- oxidative stress
- risk factors
- intensive care unit
- staphylococcus aureus
- metabolic syndrome
- pulmonary tuberculosis
- high fat diet induced
- cell cycle arrest
- multidrug resistant
- gram negative
- drug induced
- wound healing
- skeletal muscle
- cell proliferation
- induced pluripotent stem cells