Gene-silencing antisense oligomers inhibit acinetobacter growth in vitro and in vivo

J Infect Dis. 2013 Nov 15;208(10):1553-60. doi: 10.1093/infdis/jit460. Epub 2013 Oct 14.


Background: Peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) are synthetic DNA/RNA analogues that silence expression of specific genes. We studied whether PPMOs targeted to essential genes in Acinetobacter lwoffii and Acinetobacter baumannii are active in vitro and in vivo.

Methods: PPMOs were evaluated in vitro using minimum inhibitory concentration (MIC) and viability assays, and in vivo using murine pulmonary infection models with intranasal PPMO treatment.

Results: MICs of PPMOs ranged from 0.1 to 64 µM (approximately 0.6-38 µg/mL). The most effective PPMO tested was (RXR)4-AcpP, which is targeted to acpP. (RXR)4-AcpP reduced viability of A. lwoffii and A. baumannii by >10(3) colony-forming units/mL at 5-8 times MIC. Mice treated with ≥0.25 mg/kg of (RXR)4-AcpP survived longer and had less inflammation and bacterial lung burden than mice treated with a scrambled-sequence PPMO or phosphate-buffered saline. Treatment could be delayed after infection and still increase survival.

Conclusions: PPMOs targeted to essential genes of A. lwoffii and A. baumannii were bactericidal and had MICs in a clinically relevant range. (RXR)4-AcpP increased survival of mice infected with A. lwoffii or A. baumannii, even when initial treatment was delayed after infection. PPMOs could be a viable therapeutic approach in dealing with multidrug-resistant Acinetobacter species.

Keywords: Acinetobacter; MIC; PPMO; antisense; baumannii; infection; lwoffii; mouse; phosphorodiamidate morpholino oligomer; respiratory infection.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acinetobacter / drug effects*
  • Acinetobacter / genetics*
  • Acinetobacter / growth & development
  • Acinetobacter Infections / microbiology
  • Acinetobacter Infections / mortality
  • Acinetobacter Infections / therapy
  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Disease Models, Animal
  • Female
  • Gene Silencing*
  • Mice
  • Microbial Sensitivity Tests
  • Morpholinos / administration & dosage
  • Morpholinos / chemistry
  • Morpholinos / pharmacology*
  • Oligonucleotides, Antisense / administration & dosage
  • Oligonucleotides, Antisense / chemistry
  • Oligonucleotides, Antisense / genetics*
  • Pneumonia, Bacterial / microbiology
  • Pneumonia, Bacterial / mortality
  • Pneumonia, Bacterial / therapy


  • Anti-Bacterial Agents
  • Morpholinos
  • Oligonucleotides, Antisense