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Antimicrobial Agents and Chemotherapy, September 2005, p. 3810-3815, Vol. 49, No. 9
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.9.3810-3815.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Accumulation of Mutations in both gyrB and parE Genes Is Associated with High-Level Resistance to Novobiocin in Staphylococcus aureus

Pharmacology & Microbiology Research Laboratories, Dainippon Pharmaceutical Co., Ltd., Enoki 33-94, Suita, Osaka 564-0053,¹ Department of Microbiology, Kyoto Pharmaceutical University, Yamashina, Kyoto 607-8414, Japan²

Received 20 February 2005/ Returned for modification 16 April 2005/ Accepted 10 June 2005

Coumarin-resistant mutants of Staphylococcus aureus were isolated by three-step selection with novobiocin at different concentrations. Sequencing analysis of the gyrB and parE genes of the first-, second-, and third-step mutants revealed that successive point mutations first occurred specifically in the gyrB gene, followed by a point mutation in the parE gene and then an additional point mutation in the gyrB gene. These findings demonstrate that DNA gyrase is the primary target and that topoisomerase IV is the secondary target for novobiocin and that the accumulation of point mutations in both the gyrB and the parE genes is associated with high-level resistance to novobiocin in S. aureus. Moreover, our results show that the amino acid substitutions (Asp-89 to Gly and Ser-128 to Leu) found in GyrB are associated with resistance to novobiocin but not to coumermycin A1, suggesting that the interactions of novobiocin and coumermycin A1 with GyrB differ at the molecular level.

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