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Интеллектуальная Система Тематического Исследования НАукометрических данных |
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Novel Antibiotic Classes to Treat Gram-Negative Infectionsтезисы доклада
- Авторы: IPPOLITO J., WANG D., CHEN S., DALTON J., DEVITO J., FRANCESCHI F., HAMMER J., HANSELMANN R., KANYO Z., LAWRENCE L., MCCONNELL T., PAIK I., REMY J., SCHEIDEMAN M., SKRIPKIN E., TRAN J., DUFFY E.
- Сборник: 49th ICAAC Meeting, Sept. 12 - 15, 2009
- Тезисы
- Год издания: 2009
- Место издания: ASM, San Francisco, California, USA
- Первая страница: F2-861
- Аннотация: Background: Crystal structures of protein synthesis inhibitors bound to the 50S ribosome provided a molecular framework for designing de novo new antibacterial scaffolds. Microbiological profiles of diverse analogs of one new scaffold led to the identification and exploitation of molecular properties for activity against Gram-negative pathogens. Methods: Small molecule scaffolds were evaluated using a multi-copy simulation technique, MUSIC, for good ribosomal interaction energies and shape complementarity. New analogs were built and prioritized using BOMB; molecular properties were computed with QikProp. Compounds were synthesized and screened for inhibition of translation in Escherchia coli and Staphylococcus aureus systems and for target-selective competitive binding with a known ribosomal binder. Antibacterial activity was measured via CLSI standard microtiter-based assay against recent, clinically-relevant strains. Results: A biaryl scaffold showing the best predicted affinity for the targeted ribosome binding site was selected for elaboration. From an initial diverse set of 23 analogs, a tight-binding terphenyl analog was chosen to explore the breadth of antibacterial activity achievable. In 100 new analogs, 10 showed moderate activity against several strains of E. coli and Pseudomonas aeruginosa. From these, properties pointing toward Gram-negative activity were perceived. Exploiting them, several new analogs showed potency (MICs 0.5 - 8µg/mL) against E. coli, P. aeruginosa, and other key Gram-negatives, including multidrug-resistant ones. Conclusions: Using a structure-based design approach, a novel antibiotic series that inhibits many nosocomial Gram-negative pathogens has been created. This program paves the way for de novo design of additional novel scaffolds that may be tuned for a desired antibacterial spectrum and drug-like properties.
- Добавил в систему: Скрипкин Евгений Алексеевич