1. Antimicrob Agents Chemother. 2015 Aug;59(8):4750-8. doi: 10.1128/AAC.00428-15.
Epub 2015 May 26.

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 JM(1), Peyrusson F(1), Tulkens PM(1), Van Bambeke F(2).

Author information: 
(1)Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute,
Université catholique de Louvain, Brussels, Belgium. (2)Pharmacologie cellulaire 
et moléculaire, Louvain Drug Research Institute, Université catholique de
Louvain, Brussels, Belgium francoise.vanbambeke@uclouvain.be.

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.

Copyright © 2015, American Society for Microbiology. All Rights Reserved.

PMCID: PMC4505283 [Available on 2016-02-01]
PMID: 26014952  [PubMed - in process]