Discovery,characterization and comparison of inhibitors of Bacillus anthracis and Staphylococcus aureus replicative DNA helicases |
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Authors: | Daniel Aiello Marjorie H Barnes Esther E Biswas Subhasis B Biswas Shen Gu John D Williams Terry L Bowlin Donald T Moir |
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Institution: | 1. Microbiotix, Inc., One Innovation Dr., Worcester, MA 01605, USA;2. Department of Molecular Biology Univ. Medicine and Dentistry of New Jersey, Stratford, NJ 08084, USA |
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Abstract: | Antibacterial compounds with new mechanisms of action are needed for effective therapy against drug-resistant pathogens in the clinic and in biodefense. Screens for inhibitors of the essential replicative helicases of Bacillus anthracis and Staphylococcus aureus yielded 18 confirmed hits (IC50 ? 25 μM). Several (5 of 18) of the inhibitors were also shown to inhibit DNA replication in permeabilized polA-deficient B. anthracis cells. One of the most potent inhibitors also displayed antibacterial activity (MIC ~5 μg/ml against a range of Gram-positive species including bacilli and staphylococci) together with good selectivity for bacterial versus mammalian cells (CC50/MIC > 16) suitable for further optimization. This compound shares the bicyclic ring of the clinically proven aminocoumarin scaffold, but is not a gyrase inhibitor. It exhibits a mixed mode of helicase inhibition including a component of competitive inhibition with the DNA substrate (Ki = 8 μM) and is rapidly bactericidal at 4 × MIC. |
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