Masters Thesis

Inhibition of Amikacin Resistance in Bacteria by a Peptide Conjugated 2',4'-bridged Nucleic Acid-nc-dna Hybrid Oligomer.

Multidrug resistant Acinetobacter baumannii, a common etiologic agent of severe nosocomial infections in compromised hosts, usually harbors aac(6’)-Ib. This gene codes for an aminoglycoside acetyltransferase that modifies amikacin and other aminoglycosides of clinical relevance. The goal of this work was to interfere with expression of this resistance gene and induce susceptibility to amikacin in resistant pathogens. In vitro translation assays led to the identification of an antisense oligodeoxynucleotide (ODN4) that targets the initiation of translation region of aac(6’)- Ib mRNA. An isosequential nuclease-resistant chimeric oligomer composed of 2’,4’- bridged nucleic acid-NC (BNANC) residues and deoxynucleotides (BNANC -DNA) covalently bound to the cell-penetrating peptide (RXR)4XB (where “X” and “B” stand for 6-aminohexanoic acid and β-alanine, respectively). This compound, called CPPBD4, inhibited translation at similar levels observed with ODN4. Addition of a combination of Amikacin and CPPBD4 to a culture of an Acinetobacter baumannii clinical strain harboring aac(6’)-Ib resulted in growth inhibition indicating that CPPBD4 reached the cytosol and interfere with the expression of the resistance enzyme.

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