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

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https://ir.library.oregonstate.edu/concern/articles/0v8385389

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  • 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 Acinetobacter species.
  • 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.
  • Keywords: antisense, infection, respiratory infection, phosphorodiamidate morpholino oligomer, lwoffii, baumannii, oligomer, MIC, Acinetobacter, PMO, morpholino, mouse
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  • 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
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  • 208
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  • 10
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  • This work was supported by Sarepta (formerly AVI BioPharma), grants from the N. L. Tartar fund (to BLG), and the National Institutes of Health (AI098724, DEG, PI), and institutional funding from University of Texas Southwestern Medical Center (to DEG).
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