Abstract
The increasing occurrence of drug-resistant bacterial infections in the clinic has created a need for new antibacterial agents. Natural products have historically been a rich source of both antibiotics and lead compounds for new antibacterial agents. The natural product simocyclinone D8 (SD8) has been reported to inhibit DNA gyrase, a validated antibacterial drug target, by a unique catalytic inhibition mechanism of action. In this work, we have used a deconstruction-reconstruction approach to prepare analogs of the coumarin subunit of SD8 and evaluated their ability to disrupt binding of the DNA gyrase enzyme to DNA in a surface plasmon resonance assay. This has led to a minimum pharmacophore required for disruption of binding.
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Acknowledgments
Funding for this work was provided by the VCU/MCV A.D. Williams Trust Fund, the Thomas F. and Kate Miller Jeffress Memorial Trust Fund, and the VCU School of Pharmacy (to K.C.E.). The author thanks Professor Richard A. Glennon, Professor B. Frank Gupton, and Professor John C. Hackett for helpful discussions and Professor Glen Kellogg for assistance in preparing this manuscript.
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Gaskell, L.M., Nguyen, T. & Ellis, K.C. Defining a minimum pharmacophore for simocyclinone D8 disruption of DNA gyrase binding to DNA. Med Chem Res 23, 3632–3643 (2014). https://doi.org/10.1007/s00044-014-0942-z
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DOI: https://doi.org/10.1007/s00044-014-0942-z