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Experimental Therapeutics

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

Christina Lopez, Brock A. Arivett, Luis A. Actis, Marcelo E. Tolmasky
Christina Lopez
aCenter for Applied Biotechnology Studies, Department of Biological Science, California State University Fullerton, Fullerton, California, USA
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Brock A. Arivett
bDepartment of Microbiology, Miami University, Oxford, Ohio, USA
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Luis A. Actis
bDepartment of Microbiology, Miami University, Oxford, Ohio, USA
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Marcelo E. Tolmasky
aCenter for Applied Biotechnology Studies, Department of Biological Science, California State University Fullerton, Fullerton, California, USA
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DOI: 10.1128/AAC.01304-15
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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 (BNANC) residues and deoxynucleotides (BNANC-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.

FOOTNOTES

    • Received 3 June 2015.
    • Returned for modification 21 June 2015.
    • Accepted 8 July 2015.
    • Accepted manuscript posted online 13 July 2015.
  • Supplemental material for this article may be found at http://dx.doi.org/10.1128/AAC.01304-15.

  • Copyright © 2015, American Society for Microbiology. All Rights Reserved.
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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
Christina Lopez, Brock A. Arivett, Luis A. Actis, Marcelo E. Tolmasky
Antimicrobial Agents and Chemotherapy Aug 2015, 59 (9) 5798-5803; DOI: 10.1128/AAC.01304-15

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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
Christina Lopez, Brock A. Arivett, Luis A. Actis, Marcelo E. Tolmasky
Antimicrobial Agents and Chemotherapy Aug 2015, 59 (9) 5798-5803; DOI: 10.1128/AAC.01304-15
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