Mannich reaction derivatives of novobiocin with modulated physiochemical properties and their antibacterial activities |
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Authors: | Tambo-ong Arlyn Chopra Sidharth Glaser Bryan T Matsuyama Karen Tran Tran Madrid Peter B |
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Affiliation: | Center for Infectious Disease and Biodefense Research, Biosciences Division, SRI International, 333 Ravenswood Avenue, Menlo Park, CA 94025, USA. |
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Abstract: | Synthetic derivatives of the natural product antibiotic novobiocin were synthesized in order to improve their physiochemical properties. A Mannich reaction was used to introduce new side chains at a solvent-exposed position of the molecule, and a diverse panel of functional groups was evaluated at this position. Novobiocin and the new derivatives were tested for their binding to gyrase B and their antibacterial activities against Staphylococcus aureus, Mycobacterium tuberculosis, Francisella tularensis and Escherichia coli. While the new derivatives still bound the gyrase B protein potently (0.07-1.8 μM, IC(50)), they had significantly less antibacterial activity. Two compounds were identified with increased antibacterial activity against M. tuberculosis, with a minimum inhibitory concentration of 2.5 μg/ml. |
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Keywords: | Novobiocin Gyrase B Tuberculosis Antibacterial Aminocoumarin |
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