Multidrug-resistant (MDR) Acinetobacter baumannii is a problematic pathogen in New York City (NYC) hospitals and worldwide. The use of antisense nucleic acid analogs, which competitively bind targeted sequences of essential bacterial genes, is a promising strategy for the treatment of MDR bacterial infections.
A peptide nucleic acid (PNA) containing the cell-penetrating peptide (RXR)4XB bound to a 10-mer nucleic acid was designed to target the carA gene of A. baumannii. This gene, which is necessary for pyrimidine synthesis, was previously shown to be an essential gene for A. baumannii. MICs were performed in chemically defined minimal medium against 4 clinical isolates representing the dominant strains of A. baumannii in the NYC region. The in vivo activity of the PNA compound was tested in a sepsis model using Galleria mellonella caterpillars. A. baumanni strain KB17, which possesses blaOXA23 and is susceptible only to polymyxins, was used in the in vivo model. Caterpillars were inoculated with 1x106 cfu of KB17 followed 30 min later with an inoculation of phosphate-buffered saline (PBS) or the PNA compound. Survival was observed over a period of 6 days.
The MIC of the PNA compound was 1.25 μM for the 4 strains of A. baumannii. When Galleria mellonella caterpillars were given a dose of the PNA compound expected to achieve a concentration of 5 μM in the caterpillars, no effect on mortality was seen. When given a dose expected to achieve a concentration of 20 μM, mortality was reduced 53% in the experimental group compared to the PBS controls (p = 0.015).
A PNA compound targeting the carA gene of A. baumannii demonstrated both in vitro and in vivo activity against one of the dominant MDR A. baumannii strains in the NYC region. These findings are promising for the future use of antisense technology against MDR bacteria. More studies using other animal models and additional bacterial strains are needed to elucidate the true promise of this approach.
J. Quale, None
D. Landman, None