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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

Authors :
Julien M. Buyck
Frédéric Peyrusson
Paul M. Tulkens
Françoise Van Bambeke
Pharmacologie des anti-infectieux (PHAR)
Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM)
Cisbio, Research Department
CIS BIOINTERNATIONAL
Pharmacologie Cellulaire et Moléculaire [Brussels]
Louvain Drug Research Institute [Bruxelles, Belgique] (LDRI)
Université Catholique de Louvain = Catholic University of Louvain (UCL)-Université Catholique de Louvain = Catholic University of Louvain (UCL)
Université Catholique de Louvain = Catholic University of Louvain (UCL)
Source :
Antimicrobial Agents and Chemotherapy, Antimicrobial Agents and Chemotherapy, American Society for Microbiology, 2015, 59 (8), pp.4750-4758. ⟨10.1128/AAC.00428-15⟩
Publication Year :
2015
Publisher :
HAL CCSD, 2015.

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 ( E max 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. E max 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.

Details

Language :
English
ISSN :
00664804 and 10986596
Database :
OpenAIRE
Journal :
Antimicrobial Agents and Chemotherapy, Antimicrobial Agents and Chemotherapy, American Society for Microbiology, 2015, 59 (8), pp.4750-4758. ⟨10.1128/AAC.00428-15⟩
Accession number :
edsair.doi.dedup.....afd919092c25f4c1689b8061729d4024
Full Text :
https://doi.org/10.1128/AAC.00428-15⟩