This article is published by Oxford University Press on behalf of the Infectious Diseases Society of America. This is a pre-copy-editing, author-produced PDF of an article accepted for publication in the Journal of Infectious Diseases following peer review. The definitive publisher-authenticated version, Geller, B. L., Marshall-Batty, K., Schnell, F. J., McKnight, M. M., Iversen, P. L., & Greenberg, D. E. (2013). Gene-Silencing Antisense Oligomers Inhibit Acinetobacter Growth In Vitro and In Vivo. Journal of Infectious Diseases, 208(10), 1553-1560. doi:10.1093/infdis/jit460, is available online at: http://jid.oxfordjournals.org/content/208/10/1553.full.pdf?keytype=ref&ijkey=qepbqtxt5pt.
Background: Peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) are
synthetic DNA/RNA analogs that silence expression of specific genes. We studied whether
PPMOs targeted to essential genes in Acinetobacter lwoffii and A. baumannii are active in
vitro and in vivo.
Methods: PPMOs were evaluated in vitro using MIC and viability assays, and in vivo using
murine pulmonary infection models with intranasal PPMO treatment.
Results: MICs of PPMOs ranged from 0.1 and 64 μM (~0.6 to 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 > 10³ cfu/ml at 5 to 8 x MIC. Mice treated with 0.25 mg/kg
or more of (RXR)₄-AcpP survived longer and had less inflammation and bacterial lung
burden than mice treated with a scrambled-sequence PPMO or PBS. 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
Geller, B. L., Marshall-Batty, K., Schnell, F. J., McKnight, M. M., Iversen, P. L., & Greenberg, D. E. (2013). Gene-Silencing Antisense Oligomers Inhibit Acinetobacter Growth In Vitro and In Vivo. Journal of Infectious Diseases, 208(10), 1553-1560. doi:10.1093/infdis/jit460