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Ribosomal Target Modifications Designed to Evaluate the Potency of Enhanced Macrolidesтезисы доклада
- Авторы: KANYO Z., BHATTACHARJEE A., BORTOLON E., CHANTHAVONG F., CHEN S., DALTON J., DEVITO J., DU Y., FARMER J., FRANCESCHI F., GOULD T., JOB G., O'DOWD H., IPPOLITO J., LAWRENCE L., LOU R., LOU S., MARTYNOW J., MCCONNELL T., SKRIPKIN E., TANG Y., TOWKEOGH C., WU Y., DUFFY E.
- Сборник: 50th ICAAC Meeting, Sept. 12-15, 2010
- Тезисы
- Год издания: 2010
- Место издания: ASM Boston, Massachusetts
- Первая страница: F1-2153
- Аннотация: Background: Crystal structures of early enhanced macrolide antibiotics bound to the Haloarcula marismortui 50S ribosomal subunit and the computational analysis thereof, have afforded such a dramatic increase in the target potency of subsequent macrolides that in vitro translation inhibition assays of naturally occurring targets are not useful for driving structure activity relationships (SAR). A series of mutant ribosomes have been specifically designed to adversely impact macrolide binding in order to address this issue within our enhanced macrolide program. Methods: A residue-by-residue energetic analysis of the bound structure of azithromycin was produced using MCPRO and employed along with known resistance sites to identify contact bases. These were mutated singly and in combination to produce ribosomes resistant to both common as well as enhanced macrolides. Molecules were designed using BOMB, synthesized and evaluated. Translation inhibition in wild-type, resistant and hyper resistant ribosomes served as a surrogate for binding affinity. MICs against bacterial strains were performed according to CLSI methods. Results: A ribosome double mutant, A2058G, A2059G, afforded a range of translation IC50s from <0.02 ∝m to >100 ∝m against a variety of enhanced macrolides. Other ribosome mutant combinations were too resistant or too susceptible to be useful in expanding the translation IC50 range. This system was then used to develop macrolide SAR which proved critical in designing molecules active in animal models against resistant pneumococci and staphylococci, including methicillin-resistant Staphylococcus aureus. Conclusions: Enhanced ribosomal binding has produced several novel series of macrolide antibiotics demonstrating superior activity against resistant bacterial pathogens.
- Добавил в систему: Скрипкин Евгений Алексеевич