The increasing occurrence of multi drug resistant bacterial infections has underlined the urgent need for the development of new and more potent antibiotics.Bacterial RNA polymerase (RNAP) is a validated target that allows efficacy and selective toxicity.Unfortunately the efficacy of clinically used RNAP inhibitors (rifamycins) is threatened by the emergence of bacterial resistance.The recent identification of the binding region of Myxopyronin B (MyxB), a natural product antibiotic, offered us the possibility to use a structure based design approach for the identification of new drug-like RNA polymerase inhibitors. A structure-based virtual screening on the MyxB binding region was performed and we identified two compounds which showed selective inhibitory activity towards E. Coli RNAP in the micromolar range. A SAR expansion programme based upon one of these active molecules has been undertaken in order to identify the factors determining potency and selectivity and the biological results will be presented.

Design and synthesis of bacterial RNA polymerase inhibitors

245th National Meeting (2013)

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