A Comparison of Active Site Binding of 4-Quinolones and Novel Flavone Gyrase Inhibitors to DNA Gyrase

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4-Quinolone antibacterials are known to inhibit the topoisomerase II (DNA gyrase) of numerous bacterial species (among them Escherichia coli, Micrococcus luteus, Mycobacterium species, Pseudomonas aeruginosa, and Staphylococcus aureus), although to differing degrees of potency1,2,3 Optimal potency is based on the balance in structure-activity relationship between the permeability of the agent through the bacterial cell wall and membrane(s), and activity at the enzyme level.1,3 Activity is based on the observations that 4-quinolone antibacterials target the Gyr A subunit of the DNA gyrase holoenzyme,4 inhibiting supercoiling and facilitating the “cleavable complex” by inhibiting the religation of DNA gyrase holoenzymemediated sequence-specific 4-base pair staggered cuts on the DNA duplex.5 Such inhibition can be observed and quantitated by running either the in vitro DNA gyrase supercoiling inhibition assay or the “cleavable complex” DNA gyrase assay.6,7