RX-P873

The pyrrolocytosine RX-P873, a new broad-spectrum antibiotic in preclinical development, inhibits protein synthesis at the translation step. The aims of this work were to study RX-P873's ability to accumulate in eukaryotic cells, together with its activity against extracellular and intracellular forms of infection by Staphylococcus aureus and Pseudomonas aeruginosa , using a pharmacodynamic approach allowing the determination of maximal relative efficacies ( Emax values) and bacteriostatic concentrations ( C s values) on the basis of Hill equations of the concentration-response curves. RX-P873's apparent concentration in human THP-1 monocytes was about 6-fold higher than the extracellular one. In broth, MICs ranged from 0.125 to 0.5 mg/liter ( S. aureus ) and 2 to 8 mg/liter ( P. aeruginosa ), with no significant shift in these values against strains resistant to currently used antibiotics being noted. In concentration-dependent experiments, the pharmacodynamic profile of RX-P873 was not influenced by the resistance phenotype of the strains. Emax values (expressed as the decrease in the number of CFU from that in the initial inoculum) against S. aureus and P. aeruginosa reached more than 4 log units and 5 log units in broth, respectively, and 0.7 log unit and 2.7 log units in infected THP-1 cells, respectively, after 24 h. C s values remained close to the MIC in all cases, making RX-P873 more potent than antibiotics to which the strains were resistant (moxifloxacin, vancomycin, and daptomycin for S. aureus ; ciprofloxacin and ceftazidime for P. aeruginosa ). Kill curves in broth showed that RX-P873 was more rapidly bactericidal against P. aeruginosa than against S. aureus . Taken together, these data suggest that RX-P873 may constitute a useful alternative for infections involving intracellular bacteria, especially Gram-negative species.

RX-P873 is a novel antibiotic from the pyrrolocytosine series which exhibits high binding affinity for the bacterial ribosome and broad-spectrum antibiotic properties. The pyrrolocytosines have shown in vitro activity against multidrug-resistant Gram-negative and Gram-positive strains of bacteria known to cause complicated urinary tract, skin, and lung infections, as well as sepsis. Enterobacteriaceae (657), Pseudomonas aeruginosa (200), and Acinetobacter baumannii (202) isolates from North America and Europe collected in 2012 as part of a worldwide surveillance program were tested in vitro by broth microdilution using Clinical and Laboratory Standards Institute (CLSI) methodology. RX-P873 (MIC 90 , 0.5 μg/ml) was >32-fold more active than ceftazidime and inhibited 97.1% and 99.5% of Enterobacteriaceae isolates at MIC values of ≤1 and ≤4 μg/ml, respectively. There were only three isolates with an MIC value of >4 μg/ml (all were indole-positive Protea ). RX-P873 (MIC 50/90 , 2/4 μg/ml) was highly active against Pseudomonas aeruginosa isolates, including isolates which were nonsusceptible to ceftazidime or meropenem. RX-P873 was 2-fold less active against P. aeruginosa than tobramycin (MIC 90 , 2 μg/ml; 91.0% susceptible) and colistin (MIC 90 , 2 μg/ml; 99.5% susceptible) and 2-fold more potent than amikacin (MIC 90 , 8 μg/ml; 93.5% susceptible) and meropenem (MIC 90 , 8 μg/ml; 76.0% susceptible). RX-P873, the most active agent against Acinetobacter baumannii (MIC 90 , 1 μg/ml), was 2-fold more active than colistin (MIC 90 , 2 μg/ml; 97.0% susceptible) and 4-fold more active than tigecycline (MIC 90 , 4 μg/ml). This novel agent merits further exploration of its potential against multidrug-resistant Gram-negative bacteria.