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Antimicrobial Agents and Chemotherapy, March 2003, p. 941-947, Vol. 47, No. 3
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.3.941-947.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Alteration of Escherichia coli Topoisomerase IV to Novobiocin Resistance

Christine D. Hardy and Nicholas R. Cozzarelli*

Department of Molecular and Cell Biology, University of California, Berkeley, California 94720-3204

Received 2 December 2002/ Accepted 10 December 2002

DNA gyrase and topoisomerase IV (topo IV) are the two essential type II topoisomerases of Escherichia coli. Gyrase is responsible for maintaining negative supercoiling of the bacterial chromosome, whereas topo IV's primary role is in disentangling daughter chromosomes following DNA replication. Coumarins, such as novobiocin, are wide-spectrum antimicrobial agents that primarily interfere with DNA gyrase. In this work we designed an alteration in the ParE subunit of topo IV at a site homologous to that which confers coumarin resistance in gyrase. This parE mutation renders the encoded topo IV approximately 40-fold resistant to inhibition by novobiocin in vitro and imparts a similar resistance to inhibition of topo IV-mediated relaxation of supercoiled DNA in vivo. We conclude that topo IV is a secondary target of novobiocin and that it is very likely to be inhibited by the same mechanism as DNA gyrase.

* Corresponding author. Mailing address: Department of Molecular and Cell Biology, University of California, 401 Barker Hall, Berkeley, CA 94720-3204. Phone: (510) 642-5266. Fax: (510) 643-1079. E-mail: ncozzare{at}socrates.berkeley.edu.

Antimicrobial Agents and Chemotherapy, March 2003, p. 941-947, Vol. 47, No. 3
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.3.941-947.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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