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

Bruce L Geller1, Kimberly Marshall-Batty, Frederick J Schnell

  • 1Department of Microbiology, Oregon State University.

The Journal of Infectious Diseases
|October 17, 2013
PubMed
Abstract

Insights

Peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) targeting essential genes in Acinetobacter species show promise as a new antibiotic. These PPMOs were effective in vitro and in vivo, increasing survival in a mouse model of infection.

Area of Science:

  • Microbiology
  • Antimicrobial Research
  • Molecular Biology

Background:

  • Peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) are synthetic nucleic acid analogs designed to silence specific gene expression.
  • Acinetobacter species, including A. lwoffii and A. baumannii, are significant opportunistic pathogens, often exhibiting multidrug resistance.

Purpose of the Study:

  • To evaluate the in vitro and in vivo efficacy of PPMOs targeting essential genes in Acinetobacter lwoffii and Acinetobacter baumannii.
  • To assess the potential of PPMOs as a therapeutic strategy against multidrug-resistant Acinetobacter infections.

Main Methods:

  • In vitro studies involved minimum inhibitory concentration (MIC) and viability assays to determine PPMO effectiveness.
  • In vivo efficacy was assessed using murine pulmonary infection models with intranasal PPMO administration.
  • Survival rates, inflammation, and bacterial lung burden were measured in treated and control mice.

Main Results:

  • PPMOs demonstrated bactericidal activity with MICs in a clinically relevant range (0.1 to 64 µM).
  • The PPMO (RXR)4-AcpP, targeting the acpP gene, significantly reduced bacterial viability.
  • Mice treated with (RXR)4-AcpP showed increased survival, reduced lung inflammation, and lower bacterial burden, even with delayed treatment.

Conclusions:

  • PPMOs targeting essential genes are effective bactericidal agents against Acinetobacter species.
  • (RXR)4-AcpP significantly improved survival in a mouse model of Acinetobacter infection.
  • PPMOs represent a promising therapeutic approach for combating multidrug-resistant Acinetobacter infections.
Keywords:
AcinetobacterMICPPMOantisensebaumanniiinfectionlwoffiimousephosphorodiamidate morpholino oligomerrespiratory infection

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