title: 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.
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 infection by Staphylococcus aureus and Pseudomonas aeruginosa, using a pharmacodynamic approach allowing the determination of maximal relative efficacies (Emax values) and bacteriostatic concentrations (Cs 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. 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, 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.
authors.affiliation: Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Julien M
authors.initials: JM
authors.lastname: Buyck
authors.affiliation: Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Peyrusson
authors.affiliation: Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Paul M
authors.identifier: http://orcid.org/0000-0002-7121-3623
authors.initials: PM
authors.lastname: Tulkens
authors.affiliation: Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium francoise.vanbambeke@uclouvain.be.
authors.forename: Françoise
authors.identifier: http://orcid.org/0000-0002-0052-7991
authors.initials: F
authors.lastname: Van Bambeke
mesh_terms: D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D002442:Ceftazidime / Q000627:therapeutic use; D002478:Cells, Cultured; D002939:Ciprofloxacin / Q000627:therapeutic use; D017576:Daptomycin / Q000627:therapeutic use; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects; D024841:Fluoroquinolones / Q000627:therapeutic use; D006146:Guanidines / Q000627:therapeutic use*; D006801:Humans; D008826:Microbial Sensitivity Tests / Q000379:methods; D009000:Monocytes / Q000382:microbiology*; D000077266:Moxifloxacin; D011500:Protein Synthesis Inhibitors / Q000627:therapeutic use*; D011552:Pseudomonas Infections / Q000188:drug therapy*; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D011744:Pyrimidinones / Q000627:therapeutic use*; D013203:Staphylococcal Infections / Q000188:drug therapy*; D013211:Staphylococcus aureus / Q000187:drug effects*; D014640:Vancomycin / Q000627:therapeutic use
chemical_list: D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D006146:Guanidines; D011500:Protein Synthesis Inhibitors; D011744:Pyrimidinones; C000603506:RX-P873; D002939:Ciprofloxacin; D014640:Vancomycin; D002442:Ceftazidime; D017576:Daptomycin; D000077266:Moxifloxacin