4-Quinolone Resistance Mutations in the DNA Gyrase of Escherichia coli Clinical Isolates Identified by Using

Seven nalidixic acid-resistant clinical isolates of Escherichia coli were shown to carry resistance mutations in their gyrase A proteins. Six had serine-83 to leucine or tryptophan changes; the seventh had an aspartate-87 to valine substitution. The frequent occurrence of a mutation at serine-83 implies a key role for this residue in quinolone action. Antimicrobial 4-quinolones exert their potent antagonistic effects on bacterial DNA replication by inhibiting DNA gyrase, an A2B2 tetrameric enzyme that catalyzes ATP-dependent DNA supercoiling (4, 6-8, 10, 13, 23). Gyrase promotes the negative supercoiling of DNA and the forma-tion and resolution of interlocked DNA circles and knotted DNA by passing a DNA duplex through a transient enzyme-bridged double-strand break in DNA (22). Studies with purified Escherichia coli DNA gyrase have shown that quinolones interfere with DNA breakage and reunion medi-ated by Tyr-122 of the 875-residue gyrase A subunits (6, 12)