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Inhibition of AAC(6′)-Ib-Mediated Resistance to Amikacin in Acinetobacter baumannii

Christina Lopez, Brock A. Arivett, Luis A. Actis and Marcelo E. Tolmasky
12/12/2018
Antimicrob. Agents Chemotherapy
A new type of BNA/DNA-peptide conjugate has been developed for the treatment of drug-resistant infections. This new BNA/DNA-peptide conjugate is thought to become a useful antimicrobial and chemotherapeutic agent. Lopez et al. (2015) recently published a paper where a new type of BNANC-DNA-peptide conjugate was investigated for its use as an antisense agent for the treatment of amikacin resistant infections. The research group tested a BNANC-DNA hybrid co-oligomer conjugated to a cell permeable peptide mimic named CPPBD4 for its ability to reduce the level of resistance in A. baumannii A 155 cells. 

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.