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

Bruce L. Geller, Kimberly Marshall-Batty, Frederick J. Schnell, Mattie M. McKnight, Patrick L. Iversen, David E. Greenberg

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

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 >103 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.

Original languageEnglish (US)
Pages (from-to)1553-1560
Number of pages8
JournalJournal of Infectious Diseases
Volume208
Issue number10
DOIs
StatePublished - Nov 15 2013

Fingerprint

Morpholinos
Acinetobacter
Gene Silencing
Acinetobacter baumannii
Growth
Essential Genes
Microbial Sensitivity Tests
Infection
In Vitro Techniques
Pneumonia
Stem Cells
Phosphates
RNA
Gene Expression
Lung
Peptides

Keywords

  • Acinetobacter
  • Antisense
  • Baumannii
  • Infection
  • Lwoffii
  • MIC
  • Mouse
  • Phosphorodiamidate morpholino oligomer
  • Ppmo
  • Respiratory infection

ASJC Scopus subject areas

  • Infectious Diseases
  • Immunology and Allergy

Cite this

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. https://doi.org/10.1093/infdis/jit460

Gene-silencing antisense oligomers inhibit acinetobacter growth in vitro and in vivo. / Geller, Bruce L.; Marshall-Batty, Kimberly; Schnell, Frederick J.; McKnight, Mattie M.; Iversen, Patrick L.; Greenberg, David E.

In: Journal of Infectious Diseases, Vol. 208, No. 10, 15.11.2013, p. 1553-1560.

Research output: Contribution to journalArticle

Geller, BL, Marshall-Batty, K, Schnell, FJ, McKnight, MM, Iversen, PL & Greenberg, DE 2013, 'Gene-silencing antisense oligomers inhibit acinetobacter growth in vitro and in vivo', Journal of Infectious Diseases, vol. 208, no. 10, pp. 1553-1560. https://doi.org/10.1093/infdis/jit460
Geller, Bruce L. ; Marshall-Batty, Kimberly ; Schnell, Frederick J. ; McKnight, Mattie M. ; Iversen, Patrick L. ; Greenberg, David E. / Gene-silencing antisense oligomers inhibit acinetobacter growth in vitro and in vivo. In: Journal of Infectious Diseases. 2013 ; Vol. 208, No. 10. pp. 1553-1560.
@article{af1f2363cf9e4b97bd2eb04d869c1c7e,
title = "Gene-silencing antisense oligomers inhibit acinetobacter growth in vitro and in vivo",
abstract = "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 >103 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, Antisense, Baumannii, Infection, Lwoffii, MIC, Mouse, Phosphorodiamidate morpholino oligomer, Ppmo, Respiratory infection",
author = "Geller, {Bruce L.} and Kimberly Marshall-Batty and Schnell, {Frederick J.} and McKnight, {Mattie M.} and Iversen, {Patrick L.} and Greenberg, {David E.}",
year = "2013",
month = "11",
day = "15",
doi = "10.1093/infdis/jit460",
language = "English (US)",
volume = "208",
pages = "1553--1560",
journal = "The Journal of infectious diseases",
issn = "0022-1899",
publisher = "Oxford University Press",
number = "10",

}

TY - JOUR

T1 - Gene-silencing antisense oligomers inhibit acinetobacter growth in vitro and in vivo

AU - Geller, Bruce L.

AU - Marshall-Batty, Kimberly

AU - Schnell, Frederick J.

AU - McKnight, Mattie M.

AU - Iversen, Patrick L.

AU - Greenberg, David E.

PY - 2013/11/15

Y1 - 2013/11/15

N2 - 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 >103 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.

AB - 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 >103 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.

KW - Acinetobacter

KW - Antisense

KW - Baumannii

KW - Infection

KW - Lwoffii

KW - MIC

KW - Mouse

KW - Phosphorodiamidate morpholino oligomer

KW - Ppmo

KW - Respiratory infection

UR - http://www.scopus.com/inward/record.url?scp=84888582855&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84888582855&partnerID=8YFLogxK

U2 - 10.1093/infdis/jit460

DO - 10.1093/infdis/jit460

M3 - Article

VL - 208

SP - 1553

EP - 1560

JO - The Journal of infectious diseases

JF - The Journal of infectious diseases

SN - 0022-1899

IS - 10

ER -