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Optimization of Gyrase Inhibitors

Mihael FlorjaničAndreja MajerleMarko OblakAndreja PlaperPrimož PristovšekMiloš Ružič

出版	2004
URL	http://books.google.com.hk/books?id=5oJmrgEACAAJ&hl=&source=gbs_api

註釋

Increasing bacterial resistance to conventional antibiotics requires development of novel antimicrobial substances. Knowledge of tertiary structures of bacterial proteins - potential drug targets and libraries of organic compounds nowadays enable targeted development of novel antimicrobials. Within the scope of this project we propose to develop novel specific inhibitors of bacterial gyrases. Design of novel compounds will be designed based on molecular modeling and screening results of a number of organic compounds with NMR methods (similar to ĆSAR by NMRĆ approach) in the presence of isotopically labeled recombinant gyrase fragment, where compounds with low to moderate affinity to the active site of gyrase are identified and are later combined into novel compounds with increased potency. Assignment of bacterial gyrase B fragment, prepared in the preceding project will be used for analysis of NMR measurements, while inhibition will be tested also with other spectroscopic and biochemical methods. For the purpose of testing specificity of compounds a recombinant human topoisomerase II will be expressed in yeast and purified. Based on molecular modeling of docking into the gyrase with modeling of the corresponding domain of human topo II and organic synthesis we will prepare novel, more selective compounds and test them for their inhibitory activity both in vitro in the enzymatic assay as well as in vivo on microorganisms.