|
ИСТИНА |
Войти в систему Регистрация |
Интеллектуальная Система Тематического Исследования НАукометрических данных |
||
Designer Oxazolidinones Bind to the 50S Peptidyl-Transferase Region and Can Overcome Ribosome-Based Linezolid Resistanceтезисы доклада
- Авторы: SKRIPKIN E., MCCONNEL T., KING B., DEVITO J., FRANCESCHI F., SUTCLIFFE J.
- Сборник: 45th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), December 16 – 19, 2005
- Тезисы
- Год издания: 2005
- Место издания: ASM, Washington, DC, USA
- Первая страница: F-1255
- Аннотация: Background: Rx-01_423 is a member of a family of designer oxazolidinones having potent in vitro and in vivo activity against community-acquired pathogens, including atypical respiratory pathogens, and Gram-positive pathogens. Linezolid, the first marketed oxazolidinone, has been shown to bind rather weakly to the bacterial 50S ribosomal subunit in a site that overlaps the binding site for chloramphenicol. We compared the 50S ribosomal binding affinity of Rx-01_423 to that of linezolid.? Methods: The ability of Rx-01_423 and linezolid to inhibit translation were compared in an in vitro translation assay with ribosomes purified either from wild type Staphylococcus aureus QC or S. aureus A7820, a strain that is resistant to both linezolid and macrolides (LinR (Erm)C). The binding affinity of Rx-01_423 and linezolid was compared using a competition binding assay based on the ability of oxazolidinones to displace radioactively labeled chloramphenicol. Results: The IC50s of Rx-01_423 vs. wt and LinR (Erm)C S. aureus were <0.020 µM and 0.07 µM, respectively, while the IC50s for linezolid were 0.9 µM and 9 µM, respectively. The chloramphenicol displacement assay confirmed that Rx-01_423 is able to displace chloramphenicol. This compounds displace chloramphenicol 20-fold stronger than linezolid. The specificity of Rx-01_423 for prokaryotic (S. aureus wt) vs eukaryotic (rabbit reticulocyte) ribosomes is comparable to that of linezolid; both show a ratio of IC50s >100. Conclusion: 1) Rx-01_423 bound to bacterial 50S subunits, competing with chloramphenicol for its binding site. 2) Using our structure-based design platform, we identified the RX-01 family of compounds that were more strongly bound than linezolid to 50S. 3) The RX-01 family of compounds is able to overcome linezolid and macrolide ribosome-based resistance mechanisms.
- Добавил в систему: Скрипкин Евгений Алексеевич