Oxazolidinone antibiotics

Proliferation Inhibitor of DNA polymerase-gamma (e.g., nucleoside reverse transcriptase inhibitors) inhibition of mitochondrial protein synthesis (e.g., oxazolidinone antibiotics) mitochondrial DNA mutation (e.g.. oxidative injury by ethanol)... 

In many ways, mitochondria resemble bacteria for example, the mitochondrial ribosomal RNA genes of all eukaryotes have been traced back to the eubacteria [10]. This can explain why some antibacterial compounds with the target of inhibiting bacterial protein synthesis also inhibit mitochondrial protein synthesis [6, 11, 12], resulting in hematotoxicity. Tetracycline, chloramphemcol and some oxazolidinone antibiotics have been shown to induce hematotoxicity by inhibiting mitochondrial protein synthesis [13]. 

These antibiotics are considered as a choice of last resort where every other antibiotic therapy has failed. The first and only commercially available oxazolidinone antibiotic is linezolid which was introduced in 2002. Its mechanism of action is inhibition of bacterial protein synthesis. It is available for intravenous administration and also has the advantage of having excellent oral bioavailability. Linezolid is used for the treatment of infections caused by multi-resistant bacteria including streptococcus and methicillin-resistant Staphylococcus aureus (MRS A). 

Linezolid s a novel oxazolidinone antibiotic with exclusively Gram-positive activity (including MRSA) which acts at the level of the 30S and 70S ribosomal subunits by a unique mechanism it inhibits protein synthesis by preventing formation of initiation complexes. Linezolid has excellent oral bioavailability and tissue penetration the most important adverse effect is marrow suppression which is usually reversible. Its major indications are soft tissue infections and nosocomial pneumonia, although these will probably expand in the future. 

Further work in the area of the structural characterization of impurities and degradants of pharmaceuticals was also reported from the author s laboratories in 1999.107 First, the susceptibility of the morpholine substituent in the oxazolidinone antibiotic linezolid (41) was characterized using micro-NMR probe capabilities. Beginning from linezolid (41) photo-oxidation produced a transient pink color in... 

The author and a co-worker later exploited 3 mm NMR probe capabilities in a study of the thermal degradation products of the oxazolidinone antibiotic Zyvox (linezolid, 41) based on the use of H-15N heteronuclear shift correlation experiments.127 In a study of the structure-function relationships of a new growth hormone-releasing peptide, ghrelin, Bednarek and co-workers128 at Merck utilized micro-probe capabilities in the characterization of the structures of the minimum sequence of ghrelin necessary for activity. As a result of these efforts, a small spiroindan, MK-0677 (59) with oral bioavailability was found to be one of the most potent synthetic analogs with this activity. 

Finally, it has to be noted that glycopeptides only represent one option to combat infections by gram-positive bacteria. Current research is focused on other cell wall biosynthesis inhibitors (e.g., (3-lactams, cephalosporins) or even on the development of antibacterial agents (e.g., tetracyclines, ketohdes, and quinolone antibiotics) against other targets.An important drug candidate in this context is hnezolid (Zyvox), which is an entirely synthetic oxazolidinone antibiotic with in vitro and in vivo efficiency against MRS A and VRE. ... 

Thermal degradation pathway products of the oxazolidinone antibiotic Zyvox . In a study of the degradation chemistry of the drug Zyvox, the first member of a new class of oxazolidinone antibiotics, Hadden et al. utilized long-range GHMBC data to... 

Synthesis ofquinolone antibiotics The oxazolidinone antibiotics The synthesis of anti-viral nucleoside analogues The New Chiral Pool... 

The azide 33 is readily transformed into the convenient reagent 38 which has been incorporated into a final intermediate 38 in the synthesis of the oxazolidinone antibiotic 39.14... 

Figure 5 The pharmacophore for the oxazolidinone antibiotics. This is a cutaway view of the sterically forbidden region defining the shape of the binding site.

The past decades witnessed a major decrease in the number of newly discovered compounds. In an almost 40-year period (1962-2000), no new class of antibiotic was introduced to the market (nalidixic acid in 1962, the oxazolidinone antibiotic linezolid in 2000) [44, 45]. The major reason for the decrease in the number of newly discovered compounds might be a decline in screening efforts [37]. Ironically, some of the leading pharmaceutical companies are currently cutting back their antiinfective programs, especially for natural products [46]. They rather focus their activities on the semisynthetic modification of existing antibiotics to produce second- and third-generation antibiotics with improved properties. 

Antal EJ, Hendershot PE, Batts DH, Sheu W-P, Hopkins NK, Donaldson KM Linezohd, a novel oxazolidinone antibiotic assessment of monoamine oxidase inhibition using presscr response to oral tyramine. JC wP/ranwaco/ (2001) 41, 552-62. 

Radezolid is an oxazolidinone antibiotic used for treating acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP) [135]. It has been given QIDP (Qualified Infectious Disease Product) status by USFDA (Scheme 2.14). 

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