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Existing lead compounds will be prioritized on the basis of their potential for chemical optimization and mechanism type. Combinatorial and/or focused libraries will be prepared and screened for the most promising template series and structure-activity relationships (SAR) developed. Chemical optimization will be performed with respect to potency, selectivity against mammalian enzymes, in silico and experimental ADME parameters, and uptake by bacterial cells. Potential drug candidates will be evaluated in animal and cell-based model systems for efficacy and toxicity.
Professor; Biochemistry; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2001; Project Start 01-FEB-1998; Project End 31-JAN-2003 Summary: Five decades ago the introduction modern antibiotics began a revolution in effective therapy for infectious diseases. Today those advances in chemotherapy are in jeopardy due to the increasingly common appearance of drug resistant strains of microorganisms. The treatment of increasing numbers of immunocompromised individuals represents at once a clinical challenge that must be met and a venue for the 28 Antibiotics selection of new, more resistant strains.
2. Examine mutations in nonsense-mediated mRNA decay (NMD) for their effects on mRNA stability and AAP-termination codon recognition. NMD mutations eliminate regulation by the uORF-encoded AAP in vivo. 3. Identify additional transacting genes important for translational control by examining mutations in fungi that affect Arg-specific regulation or translation in vivo for their effects on AAP-mediated ribosome stalling in vitro. Cloning and identification of the genes and analysis of their functions should provide a rational explanation of the mutations.
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