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Antimicrob Agents Chemother. 2015 Sep;59(9):5798-803. doi: 10.1128/AAC.01304-15. Epub 2015 Jul 13.

Inhibition of AAC(6')-Ib-mediated resistance to amikacin in Acinetobacter baumannii by an antisense peptide-conjugated 2',4'-bridged nucleic acid-NC-DNA hybrid oligomer.

Author information

1
Center for Applied Biotechnology Studies, Department of Biological Science, California State University Fullerton, Fullerton, California, USA.
2
Department of Microbiology, Miami University, Oxford, Ohio, USA.
3
Center for Applied Biotechnology Studies, Department of Biological Science, California State University Fullerton, Fullerton, California, USA mtolmasky@fullerton.edu.

Abstract

Multiresistant Acinetobacter baumannii, a common etiologic agent of severe nosocomial infections in compromised hosts, usually harbors aac(6')-Ib. This gene specifies resistance to amikacin and other aminoglycosides, seriously limiting the effectiveness of these antibiotics. An antisense oligodeoxynucleotide (ODN4) that binds to a duplicated sequence on the aac(6')-Ib mRNA, one of the copies overlapping the initiation codon, efficiently inhibited translation in vitro. An isosequential nuclease-resistant hybrid oligomer composed of 2',4'-bridged nucleic acid-NC (BNA(NC)) residues and deoxynucleotides (BNA(NC)-DNA) conjugated to the permeabilizing peptide (RXR)4XB ("X" and "B" stand for 6-aminohexanoic acid and β-alanine, respectively) (CPPBD4) inhibited translation in vitro at the same levels observed in testing ODN4. Furthermore, CPPBD4 in combination with amikacin inhibited growth of a clinical A. baumannii strain harboring aac(6')-Ib in liquid cultures, and when both compounds were used as combination therapy to treat infected Galleria mellonella organisms, survival was comparable to that seen with uninfected controls.

PMID:
26169414
PMCID:
PMC4538503
DOI:
10.1128/AAC.01304-15
[Indexed for MEDLINE]
Free PMC Article

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