RX-P873, a novel protein synthesis inhibitor, accumulates in human THP-1 monocytes and is active against intracellular infections by Gram-positive (Staphylococcus aureus) and Gram-negative (Pseudomonas aeruginosa) bacteria.

Buyck, Julien M;Peyrusson, Frédéric;Tulkens, Paul M.;Van Bambeke, Françoise
(2015) Antimicrobial Agents and Chemotherapy — Vol. 59, p. AAC (2015)

Files

Buyck-2015-2-RxP873.pdf
  • Restricted Access
  • Adobe PDF
  • 641.23 KB
Request a copy

Details

Authors
  • Buyck, Julien M
    Author
  • Peyrusson, FrédéricUCLouvain
    Author
  • Tulkens, Paul M.UCLouvain
    Author
  • Van Bambeke, Françoiseorcid-logo
    Author
Abstract
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 infections by Staphylococcus aureus and Pseudomonas aeruginosa, using a pharmacodynamic approach allowing the determination of maximal relative efficacies [Emax] and bacteriostatic concentrations [Cs] based on Hill equations of 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/L (S. aureus) and 2 to 8 mg/L (P. aeruginosa), with no significant shift in these values against strains resistant to currently-used antibiotics. In concentration-dependent experiments, the pharmacodynamic profile of RX-P873 was not influenced by the resistance phenotype of the strains. Emax values (expressed as CFU decrease from the initial inoculum) against S. aureus and P. aeruginosa reached more than 4 log and 5 log in broth, respectively, and 0.7 log and 2.7 log in infected THP-1 cells, respectively, after 24 h. Cs values remained close to the MIC in all cases, making RX-P873 more potent than antibiotics to which the strains were resistant (moxifloxacin, vancomycin, daptomycin for S. aureus; ciprofloxacin, 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.
Affiliations

Citations

  • APA
  • Chicago
  • FWB

Buyck, J. M., Peyrusson, F., Tulkens, P. M., & Van Bambeke, F. (2015). RX-P873, a novel protein synthesis inhibitor, accumulates in human THP-1 monocytes and is active against intracellular infections by Gram-positive (Staphylococcus aureus) and Gram-negative (Pseudomonas aeruginosa) bacteria. Antimicrobial Agents and Chemotherapy, 59, AAC. https://doi.org/10.1128/AAC.00428-15 (Original work published 2015)