Design at the atomic level: Generation of novel hybrid biaryloxazolidinones as promising new antibiotics

Zhou, Jiacheng; Bhattacharjee, Ashoke; Chen, Shili; Chen, Yi; Duffy, Erin M.; Farmer, Jay J.; Goldberg, Joel; Hanselmann, Roger; Ippolito, Joseph A.; Lou, Rongliang; Orbin, Alia; Oyelere, Ayomi; Salvino, Joe; Springer, Dane M.; Tran, Jennifer; Wang, Deping; Wu, Yusheng; Johnson, Graham

doi:10.1016/j.bmcl.2008.10.014

Cited by 40 publications

(29 citation statements)

References 9 publications

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“…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).…”

Section: Discussionsupporting

confidence: 83%

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

Lemaire

Kosowska-Shick

Appelbaum

et al. 2010

Antimicrob Agents Chemother

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Radezolid is a novel biaryloxazolidinone in clinical development which shows improved activity, including against linezolid-resistant strains. In a companion paper (29), we showed that radezolid accumulates about 11-fold in phagocytic cells, with ϳ60% of the drug localized in the cytosol and ϳ40% in the lysosomes of the cells. The present study examines its activity against (i) bacteria infecting human THP-1 macrophages and located in different subcellular compartments (Listeria monocytogenes, cytosol; Legionella pneumophila, vacuoles; Staphylococcus aureus and Staphylococcus epidermidis, mainly phagolysosomal), (ii) strains of S. aureus with clinically relevant mechanisms of resistance, and (iii) isogenic linezolid-susceptible and -resistant S. aureus strains infecting a series of phagocytic and nonphagocytic cells. Radezolid accumulated to similar levels (ϳ10-fold) in all cell types (human keratinocytes, endothelial cells, bronchial epithelial cells, osteoblasts, macrophages, and rat embryo fibroblasts). At equivalent weight concentrations, radezolid proved consistently 10-fold more potent than linezolid in all these models, irrespective of the bacterial species and resistance phenotype or of the cell type infected. This results from its higher intrinsic activity and higher cellular accumulation. Time kill curves showed that radezolid's activity was more rapid than that of linezolid both in broth and in infected macrophages. These data suggest the potential interest of radezolid for recurrent or persistent infections where intracellular foci play a determinant role.Intracellular infections are difficult to treat because bacteria are shielded from many of the humoral and cellular means of natural defenses while being also partially protected from the action of most antibiotics (7,12,47,58). While intracellular survival is part of the pathogenic cycle of obligatory or facultative intracellular bacteria like Listeria monocytogenes or Legionella pneumophila (7,38,51), it contributes to the recurrent or persistent character of infections caused by opportunistic intracellular bacteria like staphylococci (16). The treatment of such intracellular infections, therefore, requires the use of antibiotics that can express their activity at the site of infection. This, however, cannot be predicted simply on the basis of the ability of drugs to accumulate in cells, as several other factors may play a critical role in enhancing or impeding their local antimicrobial properties (7, 58). For example, previous work in our laboratory using a model of Staphylococcus aureus-infected THP-1 cells showed that ␤-lactams, which do not accumulate in these cells, nevertheless display significant intracellular activity provided their extracellular concentration is brought to sufficiently high but still clinically meaningful levels (31). Conversely, azithromycin, which is known to accumulate in large amounts in cells (6, 18), proves only marginally active against S. aureus phagocytosed by macrophages (1, 32). This occurs despite the fact tha...

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Section: Discussionsupporting

confidence: 83%

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

Lemaire

Kosowska-Shick

Appelbaum

et al. 2010

Antimicrob Agents Chemother

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“…Radezolid is the result of a program developed to expand the spectrum of oxazolidinones to Gram‐negative bacteria and optimize drug‐like properties 41. The program started with the observation that linezolid and sparsomycin ( 6 , a non‐selective antibiotic) had overlapping binding sites within the peptidyl transferase center of the 50S ribosomal unit (Figure 7).…”

Section: Protein Synthesis Inhibitorsmentioning

confidence: 99%

“…The strategy was therefore to link the two molecules together via an adequate bridging element and make the required structural modifications on the sparsomycin side to increase potency and selectivity 41, 44. Figure 8 shows two ( 7 and 8 ) of the numerous bridged antibiotics that were synthesized on the road to radezolid and clearly shows the evolution of the western half and the bridging unit.…”

Section: Protein Synthesis Inhibitorsmentioning

confidence: 99%

Targeting Antibiotic Resistance

2016

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Finding strategies against the development of antibiotic resistance is a major global challenge for the life sciences community and for public health. The past decades have seen a dramatic worldwide increase in human‐pathogenic bacteria that are resistant to one or multiple antibiotics. More and more infections caused by resistant microorganisms fail to respond to conventional treatment, and in some cases, even last‐resort antibiotics have lost their power. In addition, industry pipelines for the development of novel antibiotics have run dry over the past decades. A recent world health day by the World Health Organization titled “Combat drug resistance: no action today means no cure tomorrow” triggered an increase in research activity, and several promising strategies have been developed to restore treatment options against infections by resistant bacterial pathogens.

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“…Decades of studies have revealed the great diversity of molecular mechanisms used by a multitude of antibacterial agents (antibiotics) 5,6 . Atomic structures of prokaryotic ribosomes provided the basis for the development of novel antibiotics and in turn ribosome inhibitors served as tools to study protein synthesis in bacteria 7 . Similarly, the eukaryotic ribosome is a major target for broad-spectrum and eukaryote-specific small-molecule inhibitors isolated from natural sources.…”

mentioning

confidence: 99%