In Vitro Activities of the Rx-01 Oxazolidinones against Hospital and Community Pathogens

Abstract

Rx-01_423 and Rx-01_667 are two members of the family of oxazolidinones that were designed using a combination of computational and medicinal chemistry and conventional biological techniques. The compounds have a two-to eightfold-improved potency over linezolid against serious gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), multidrug-resistant streptococci, and vancomycin-resistant enterococci. This enhanced potency extends to the coverage of linezolid-resistant gram-positive microbes, especially multidrug-resistant enterococci and pneumococci. Compounds from this series expand the spectrum compared with linezolid to include fastidious gram-negative organisms like Haemophilus influenzae and Moraxella catarrhalis. Like linezolid, the Rx-01 compounds are bacteriostatic against MRSA and enterococci but are generally bactericidal against S. pneumoniae and H. influenzae.

Cellular Pharmacodynamics of the Novel Biaryloxazolidinone Radezolid: Studies with Infected Phagocytic and Nonphagocytic cells, UsingStaphylococcus aureus,Staphylococcus epidermidis,Listeria monocytogenes, andLegionella pneumophila

“…In contrast, linezolid remains static intra- cellularly for at least 5 h and shows only a modest drop in CFU in broth at 20 mg/liter. These observations are consistent with the improved interaction of radezolid with its ribosomal target (25,53,61). In spite of this, however, the maximal effects reached at 24 h are similar for radezolid and linezolid at the highest concentrations tested (if the comparison is limited to linezolid-susceptible strains).…”

“…In comparison to linezolid, it shows improved activity against a series of bacterial species capable of surviving intracellularly, such as Staphylococcus, Chlamydia, and Legionella species, and remains active against linezolid-resistant strains (25). In the companion paper, we showed that radezolid accumulates to about 12-fold-higher levels than linezolid in human THP-1 cells and localizes in lysosomes for about 40% of the total cell load, while the remainder is found in the cytosol (29).…”

Targeting Antibiotic Resistance

“…Once the optimal structural elements were determined, the activity of radezolid was assessed and it was found to bind with higher affinity to the ribosome than linezolid, which gave it enhanced antibacterial activity (2–8‐fold improvement over linezolid) against various Gram‐positive pathogens 45. Structure–activity studies of diverse oxazolidinones revealed that despite the presence of a C5 acylaminomethyl group in radezolid, it retains activity against the clinical cfr ‐positive CM05 strain of S. aureus with a minimal inhibitory concentration (MIC) value of 2 μg mL −1 , which is between those of tedizolid (0.5 μg mL −1 ) and linezolid (8 μg mL −1 ).…”

Investigational Antimicrobial Agents of 2013

“…Radezolid (Rx-01_667, RX-1741; Rib-X Pharmaceuticals) (Fig. 3, compound 8) is a novel oxazolidinone with a broader spectrum of coverage and increased antibacterial activity against Gram-positive bacteria compared to those of linezolid (102). It offers the potential for improved antibacterial activity in that it is 2-fold more active in vitro than linezolid against staphylococci and 4-to 16-fold more potent against the streptococci and enterococci.…”