ABSTRACT
Multidrug-resistant (MDR) Acinetobacter baumannii is a difficult pathogen due to its propensity to develop resistance to antibiotics. Antisense nucleic acid analogs have been proposed as a potential alternative anti-infective approach. We developed a peptide nucleic acid (PNA) compound that targets the essential Acinetobacter gene carA. The PNA oligomer was conjugated to the cell-penetrating peptide (RXR)4XB. In vitro testing of the PNA conjugate against four clinical strains of MDR-A. baumannii in minimal medium demonstrated that all four strains were inhibited at a concentration of 1.25 µM. In vivo testing of the PNA conjugate was done using a Galleria mellonella model of sepsis caused by one of the clinical strains. Preliminary testing of a variety of inocula demonstrated that an inoculum of 1 × 106 cfu was lethal to the majority of caterpillars by day 3, but not within 24 hours. The PNA compound was administered 30 minutes after an inoculum of 1 × 106 cfu at doses estimated to produce concentrations of â¼5 and 20 µM. The PNA compound had no effect at the lower dose. However, the higher dose reduced mortality from 5/28 (18%) to 0/28 (0%) at day 1 (p = 0.051) and from 19/28 (68%) to 9/28 (32%) at day 6 (p = 0.015). Antisense therapy is a novel approach to dealing with difficult MDR pathogens that could circumvent the problem of progressive resistance to available antibiotics. Further studies need to be done with additional strains and more complex in vivo model systems.
Subject(s)
Acinetobacter baumannii/drug effects , Drug Resistance, Multiple, Bacterial/drug effects , Oligodeoxyribonucleotides, Antisense/pharmacology , Peptide Nucleic Acids/pharmacology , Peptides/pharmacology , Anti-Bacterial Agents/pharmacology , Cell-Penetrating Peptides/pharmacology , Microbial Sensitivity Tests/methodsABSTRACT
Multidrug-resistant Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae are endemic to hospitals in New York City and other regions. RPX7009 is a novel ß-lactamase inhibitor with activity against serine carbapenemases. We tested the activity of meropenem plus RPX7009 against 4,500 recent Gram-negative clinical isolates from 11 New York City hospitals. The meropenem-RPX7009 combination was found to have excellent in vitro activity against Escherichia coli, K. pneumoniae, and Enterobacter spp., including multidrug-resistant (MDR) KPC-producing strains. Overall, 131/133 (98.5%) KPC-producing Enterobacteriaceae strains were inhibited by meropenem (≤1 µg/ml) plus RPX7009 (8 µg/ml). In a limited number of strains, the combination appeared to have reduced activity against KPC-producing K. pneumoniae isolates with diminished ompK35 and ompK36 expression. The addition of RPX7009 did not affect the activity of meropenem against Acinetobacter baumannii and Pseudomonas aeruginosa. The meropenem-RPX7009 combination shows promise as a novel agent against KPC-producing Enterobacteriaceae and deserves further study. Other approaches will be needed to address multidrug-resistant A. baumannii and P. aeruginosa, which typically possess different mechanisms of carbapenem resistance.
Subject(s)
Anti-Bacterial Agents/pharmacology , Boronic Acids/pharmacology , Gram-Negative Bacteria/drug effects , Heterocyclic Compounds, 1-Ring/pharmacology , Thienamycins/pharmacology , beta-Lactamase Inhibitors/pharmacology , Drug Resistance, Multiple, Bacterial/drug effects , Drug Therapy, Combination/methods , Gram-Negative Bacteria/isolation & purification , Gram-Negative Bacterial Infections/drug therapy , Hospitals , Humans , Meropenem , Microbial Sensitivity Tests/methods , New York CityABSTRACT
Imipenem with relebactam was active against Escherichia coli, Klebsiella pneumoniae, and Enterobacter spp., including K. pneumoniae carbapenemase (KPC)-producing isolates. Loss of OmpK36 in KPC-producing K. pneumoniae isolates affected the susceptibility of this combination. Enhanced activity was evident against Pseudomonas aeruginosa, including isolates with depressed oprD and increased ampC expression. However, the addition of relebactam to imipenem did not provide added benefit against Acinetobacter baumannii. The combination of imipenem with relebactam demonstrated activity against KPC-producing Enterobacteriaceae and multidrug-resistant P. aeruginosa.
