The Oxazolidinones: Past, Present, and Future

Trius Therapeutics, Inc., Department of Biology, San Diego, California 92121, USA.
Annals of the New York Academy of Sciences (Impact Factor: 4.38). 12/2011; 1241(1):48-70. DOI: 10.1111/j.1749-6632.2011.06330.x
Source: PubMed

ABSTRACT The success of linezolid stimulated significant efforts to discover new agents in the oxazolidinone class. Over a dozen oxazolidinones have reached the clinic, but many were discontinued due to lack of differentiated potency, inadequate pharmacokinetics, and safety risks that included myelosuppression. Four oxazolidinones are currently undergoing clinical evaluation. The Trius Therapeutics compound tedizolid phosphate (formerly known as torezolid phosphate, TR-701, DA-7218), the most advanced, is in phase 3 clinical trials for acute bacterial skin and skin structure infections. Rib-X completed two phase 2 studies for radezolid (Rx-01_667, RX-1741) in uncomplicated skin and skin structure infections and community-acquired pneumonia. Pfizer and AstraZeneca have each identified antitubercular compounds that have completed phase 1 studies: sutezolid (PNU-100480, PF-02341272) and AZD5847 (AZD2563), respectively. The oxazolidinones share a relatively low frequency of resistance largely due to the requirement of mutations in 23S ribosomal RNA genes. However, maintaining potency against strains carrying the mobile cfr gene poses a challenge for the oxazolidinone class, as well as other 50S ribosome inhibitors that target the peptidyl transferase center.

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    • "Mutations in the drug target site (23S rRNA or ribosomal proteins L3 and L4) are the most common mechanisms of linezolid resistance. Due to the low frequency of target mutation, the frequency of linezolid resistance is also relatively low [2]. However, emergence of the transferable linezolid resistance gene, cfr, in clinical isolates poses a challenge in linezolid treatment. "
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    ABSTRACT: Background The emergence and wide distribution of the transferable gene for linezolid resistance, cfr, in staphylococci of human and animal origins is of great concern as it poses a serious threat to the public health. In the present study, we investigated the emergence and presence of the multiresistance gene, cfr, in retail meat sourced from supermarkets and free markets of Guangzhou, China. Results A total of 118 pork and chicken samples, collected from Guangzhou markets, were screened by PCR for cfr. Twenty-two Staphylococcus isolates obtained from 12 pork and 10 chicken samples harbored cfr. The 22 cfr-positive staphylococci isolates, including Staphylococcus equorum (n = 8), Staphylococcus simulans (n = 7), Staphylococcus cohnii (n = 4), and Staphylococcus sciuri (n = 3), exhibited 17 major SmaI pulsed-field gel electrophoresis (PFGE) patterns. In 14 isolates, cfr was located on the plasmids. Sequence analysis revealed that the genetic structures (including ΔtnpA of Tn558, IS21-558, ΔtnpB, and tnpC of Tn558, orf138, fexA) of cfr in plasmid pHNTLD18 of a S. sciuri strain and in the plasmid pHNLKJC2 (including rep, Δpre/mob, cfr, pre/mob and partial ermC) of a S. equorum strain were identical or similar to the corresponding regions of some plasmids in staphylococcal species of animal and human origins. Conclusions To the best of our knowledge, this is the first study to report the presence of the multiresistance gene, cfr, in animal meat. A high occurrence of cfr was observed in the tested retail meat samples. Thus, it is important to monitor the presence of cfr in animal foods in China.
    BMC Microbiology 06/2014; 14(1):151. DOI:10.1186/1471-2180-14-151 · 2.73 Impact Factor
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    • "Radezolid was selected for further advancement with two phase 2 clinical trials completed to date: the first in CAP and the second trial in cSSSI [75]. "
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    ABSTRACT: Bacterial resistance to antibiotics is growing up day by day in both community and hospital setting, with a significant impact on the mortality and morbidity rates and the financial burden that is associated. In the last two decades multi drug resistant microorganisms (both hospital- and community-acquired) challenged the scientific groups into developing new antimicrobial compounds that can provide safety in use according to the new regulation, good efficacy patterns, and low resistance profile. In this review we made an evaluation of present data regarding the new classes and the new molecules from already existing classes of antibiotics and the ongoing trends in antimicrobial development. Infectious Diseases Society of America (IDSA) supported a proGram, called "the [prime]10 x 20[prime] initiative", to develop ten new systemic antibacterial drugs within 2020. The microorganisms mainly involved in the resistance process, so called the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa, and enterobacteriaceae) were the main targets. In the era of antimicrobial resistance the new antimicrobial agents like fifth generation cephalosporins, carbapenems, monobactams, beta-lactamases inhibitors, aminoglycosides, quinolones, oxazolidones, glycopeptides, and tetracyclines active against Gram-positive pathogens, like vancomycin-resistant S. aureus (VRSA) and MRSA, penicillin-resistant streptococci, and vancomycin resistant Enterococcus (VRE) but also against highly resistant Gram-negative organisms are more than welcome. Of these compounds some are already approved by official agencies, some are still in study, but the need of new antibiotics still does not cover the increasing prevalence of antibiotic-resistant bacterial infections. Therefore the management of antimicrobial resistance should also include fostering coordinated actions by all stakeholders, creating policy guidance, support for surveillance and technical assistance.
    Annals of Clinical Microbiology and Antimicrobials 08/2013; 12(1):22. DOI:10.1186/1476-0711-12-22 · 2.19 Impact Factor
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    ABSTRACT: Bacterial resistance to commonly used antibiotics is constantly increasing. Bacteria particularly dangerous for human life are methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium and fluoroquinolone-resistant Pseudomonas aeruginosa. Hence, there is an incessant need for developing compounds with new modes of action and seeking alternate drug targets. In this review, the authors discuss the current situation of antibacterial medicines and present data on new antibiotic targets. Moreover, alternatives to antibiotics, such as bacteriophages, antimicrobial peptides and monoclonal antibodies, are presented. The authors also draw attention to the valuable features of natural sources in developing antibacterial compounds. The need to prevent and control infections as well as the reasonable use of currently available antibiotics is also emphasized.
    Central European Journal of Biology 10/2013; 8(10). DOI:10.2478/s11535-013-0209-6 · 0.71 Impact Factor
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