Oxazolidinones resistance

Other examples include rifampin resistance due to mutations in the ipoB gene encoding the (3-subunit of RNA polymerase, or oxazolidinone resistance due to a G2576T mutation in the gene for the 23 S rRNA as central part of the 50S large ribosomal subunit. Macrolide resistance is based upon the alteration of nucleotide A2058 by a point mutation. 

Oxazolidinones are a new class of synthetic antimicrobial agents, which have activity against many important pathogens, including methicillin-resistant Staphylococcus aureus and others. Oxazolidinones (e.g. linezolid or eperezolid) inhibit bacterial protein synthesis by inhibiting the formation of the 70S initiation complex by binding to the 50S ribosomal subunit close to the interface with the 3OS subunit. 

Linezohd (Zyvox) is an oxazolidinone, a tive-membered heterocychc ring that forms the core of the hnezohd structure. The approval of hnezohd by the FDA in 2000 marked the first new structural class of antibacterial introduced into medical practice in the United States in 40 years. It is notable for its activity against methicillin-resistant Staph aureus, MRSA, and vancomycin-resistant Enterococcus faecium, VRE. It is bacteriostatic rather than bactericidal but finds significant use in patients with an intact immune system. Like several other classes of antibacterials, linezolid is an inhibitor of protein synthesis. It interacts specifically with the RNA component of a bacterial ribosome subunit to prevent initiation of protein synthesis. 

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). 

The remarkable capacity of S. aureus to develop resistance to antibiotics is no more clearly illustrated than its recently reported success against linezolid (Zyvox ). Linezoid is the first entirely new type of antibiotic (oxazolidinones) introduced in 35 years. The FDA approved it in April 2000 for the treatment of several infections including resistant strains of S. aureus. Flowever, it took only slightly more than a year for resistance to manifest itself. In the summer of 2001, the first report of staph resistance to the new antibiotic was observed in an 85-year-old man undergoing dialysis. 

Oxazolidinones are virtually neutral they do not give stable salts with acids but they can be alkylated at the nitrogen atom under basic conditions. They are rather resistant to hydrolysis vigorous treatment with alkali yields /3-amino alcohols whereas hydrochloric acid gives /3-chloroalkylamines (equation 82). The combined action of aromatic hydrocarbons and aluminum chloride on 2-oxazolidinones leads to /3-arylethylamines which are formed by alkyl-oxygen fission (equation 83) (80TL1719). 

As has been well documented elsewhere (3, 4), there was roughly a 25-year gap between the introduction of the qninolone antibiotics and the next new chemical class of antibiotics, the oxazolidinones. During this interval, innovation in antibiotic drug design and discovery was focused on the semisynthetic tailoring of natnral prodnct antibiotic scaffolds to improve pharmacologic properties and, most importantly, to overcome resistance to existing antibiotics. 

The oxazolidinones are a new class of synthetic antimicrobial agents. Produced in 1987, they were found to be active in vitro against antibiotic-susceptible and -resistant cocci and did not demonstrate cross-resistance with any other antibiotics. 

Skripkin, E., McConnell, T.S., DeVito, J., Lawrence, L., Ippolito, J.A., Duffy, E.M., Sutcliffe, J., Franceschi, F. Rx-01, a new family of oxazolidinones that overcome ribosome-based linezolid resistance. Antimicrob. Agents Chemother. 2008, 52(10), 3550. 

One solution is to make the oxazolidinone ring more resistant to hydrolysis by packing it with substituents. Among the best examples are the SuperQuats developed by Steve Davies at Oxford.23 Valine (the unnatural isomer in this case) is used to construct an oxazolidinone with two geminal methyl groups 171. We show a simple alkylation of the lithium enolate note the high yield of both the final product after hydrolysis 174 and the chiral auxiliary 171 ready for recycling. There is no endo hydrolysis nor epimerisation. 

Linezolid is an oxazolidinone that prevents the formation of a functional 70S initiation complex, which is essential to the bacterial translation process. It is indicated in the treatment of vancomycin-resistant Enterococcus faecium... 

The first of a new class of antibiotics (oxazolidinones), linezolid is active against many drug-resistant gram-positive cocci, including strains resistant to beta-lactams and vancomycin (eg, vancomycin-resistant Enterococcus faecium). Linezolid binds to a unique site on the SOS ribosomal subunit, and there is currently no cross-resistance with other protein synthesis inhibitors. Linezolid is available in both oral and parenteral formulations. 

Baizman, E.R. et al.. Antibacterial activity of synthetic analognes based on the disaccharide strnctnre of moenomycin, an inhibitor of bacterial transglycosyulase. Microbiology, 146, 3129, 2000. Bozdogan, B. and Appelbaum, PC., Oxazolidinones activity, mode of action, and mechanism of resistance, Int. J. Antimicrob. Agents, Ti, 113, 2004. 

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