Gene-silencing antisense oligomers inhibit acinetobacter growth in vitro and in vivo.
J Infect Dis
; 208(10): 1553-60, 2013 Nov 15.
Article
em En
| MEDLINE
| ID: mdl-24130069
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 >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.Palavras-chave
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Acinetobacter
/
Oligonucleotídeos Antissenso
/
Inativação Gênica
/
Morfolinos
Limite:
Animals
Idioma:
En
Revista:
J Infect Dis
Ano de publicação:
2013
Tipo de documento:
Article