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<p>Goals: The major goals of this project are to develop a new class of antibiotics that have broad-spectrum activity against pathogenic bacteria that are food-borne and infect farm animals and humans.</p><p><ol><li> Optimize an in silico approach to virtually screen modifications to DNA gyrase inhibitors (the gyramides) to increase their activity and reduce their efflux out of bacteria.</li><li> Apply the in silico approach to screen a virtual library of gyramide inhibitors for activity; identify lead compounds.</li><li> Synthesize 50 lead compounds, characterize their structures, and test their activity against a panel of 20 pathogenic bacteria that are relevant to the proposed knowledge areas.</li><li> Test the activity of the top 5 compounds against recombinant DNA gyrase and measure inhibition and binding constants.</li></ol></p>
The introduction of new antibiotics to counter emerging drug resistance will improve human and animal health. We describe the development of potent new analogs of inhibitors of 'old' antibiotics targets as a strategy for protecting animals from diseases and conditions caused by bacterial infections and protecting humans from foods contaminated by pathogenic microorganisms. It is widely recognized that antibiotic resistant bacteria emerge in confined animal feeding operations (particularly drug resistant Campylobacter and Salmonella spp.) can be transferred to humans through food. The Center for Disease Control estimates that there are ~76M cases of foodborne illness each year from viral and bacterial pathogens. The development of new classes of antibiotics--such as those described in this proposal--can relieve some of the pressure currently placed on the dwindling number of effective clinical antibiotics available for treating human infections.