title: 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.
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.
authors.affiliation: Center for Applied Biotechnology Studies, Department of Biological Science, California State University Fullerton, Fullerton, California, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Lopez
authors.affiliation: Department of Microbiology, Miami University, Oxford, Ohio, USA.
authors.forename: Brock A
authors.initials: BA
authors.lastname: Arivett
authors.affiliation: Department of Microbiology, Miami University, Oxford, Ohio, USA.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Actis
authors.affiliation: Center for Applied Biotechnology Studies, Department of Biological Science, California State University Fullerton, Fullerton, California, USA mtolmasky@fullerton.edu.
authors.forename: Marcelo E
authors.initials: ME
authors.lastname: Tolmasky
mesh_terms: D040981:Acinetobacter baumannii / Q000187:drug effects*; D000583:Amikacin / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D004247:DNA / Q000737:chemistry*; D008826:Microbial Sensitivity Tests; D010455:Peptides / Q000737:chemistry*
chemical_list: D000900:Anti-Bacterial Agents; D010455:Peptides; D000583:Amikacin; D004247:DNA