AddAB and RecBCD are related bacterial helicase/nuclease enzymes responsible for DNA repair and genetic recombination. They unwind and then hydrolyze DNA, making sequence-specific endonucleolytic scissions, and are critically important for repairing DNA double strand breaks. Mutant bacteria lacking functional helicase/nucleases are not viable in infecting mammalian hosts. Inhibitors of these enzymes may therefore be effective as antibacterial drugs, preventing DNA damage by reactive oxygen species that follow infection. No potent and selective drug-like small molecules inhibitors of AddAB and RecBCD are known, however. We herein report results of a probe development effort, within the NIH's Molecular Libraries Probe Center Network (MLPCN), to find inhibitors of AddAB and RecBCD. We discuss the uHTS results from the NIH collection (then 326,000 small molecules), hit confirmation, lead selection, and finally structural optimization to augment potency and define mechanism of action. We show two structure classes with AddAB / RecBCD activity, with  SAR studies for each series.  Molecular probes inhibiting AddAB and/or RecBCD will be useful tools in evaluating the therapeutic potential of selective and potent small molecule inhibition of bacterial helicase/nucleases.

Inhibitors of AddAB and RecBCD bacterial DNA repair enzymes: A novel class of antibiotics identified through molecular probe development efforts

245th National Meeting (2013)

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