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Antimicrobial Agents and Chemotherapy, June 2005, p. 2343-2351, Vol. 49, No. 6
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.6.2343-2351.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Biological Cost of Single and Multiple Norfloxacin Resistance Mutations in Escherichia coli Implicated in Urinary Tract Infections

Patricia Komp Lindgren,1 Linda L. Marcusson,1 Dorthe Sandvang,2 Niels Frimodt-Møller,2 and Diarmaid Hughes1*

Department of Cell and Molecular Biology, Box 596, Biomedical Center, Uppsala University, S-751 24 Uppsala, Sweden,1 Department of Microbiological R&D, Division of Microbiology, Statens Serum Institut, 5 Artillerivej, 2300 Copenhagen S, Denmark2

Received 25 October 2004/ Returned for modification 19 January 2005/ Accepted 6 February 2005

Resistance to fluoroquinolones in urinary tract infection (UTIs) caused by Escherichia coli is associated with multiple mutations, typically those that alter DNA gyrase and DNA topoisomerase IV and those that regulate AcrAB-TolC-mediated efflux. We asked whether a fitness cost is associated with the accumulation of these multiple mutations. Mutants of the susceptible E. coli UTI isolate Nu14 were selected through three to five successive steps with norfloxacin. Each selection was performed with the MIC of the selected strain. After each selection the MIC was measured; and the regions of gyrA, gyrB, parC, and parE, previously associated with resistance mutations, and all of marOR and acrR were sequenced. The first selection step yielded mutations in gyrA, gyrB, and marOR. Subsequent selection steps yielded mutations in gyrA, parE, and marOR but not in gyrB, parC, or acrR. Resistance-associated mutations were identified in almost all isolates after selection steps 1 and 2 but in less than 50% of isolates after subsequent selection steps. Selected strains were competed in vitro, in urine, and in a mouse UTI infection model against the starting strain, Nu14. First-step mutations were not associated with significant fitness costs. However, the accumulation of three or more resistance-associated mutations was usually associated with a large reduction in biological fitness, both in vitro and in vivo. Interestingly, in some lineages a partial restoration of fitness was associated with the accumulation of additional mutations in late selection steps. We suggest that the relative biological costs of multiple mutations may influence the evolution of E. coli strains that develop resistance to fluoroquinolones.

* Corresponding author. Mailing address: Department of Cell and Molecular Biology, Box 596, Biomedical Center, Uppsala University, S-751 24 Uppsala, Sweden. Phone: 46-18-471 4354. Fax: 46-18-430 396. E-mail: diarmaid.hughes{at}icm.uu.se.

Antimicrobial Agents and Chemotherapy, June 2005, p. 2343-2351, Vol. 49, No. 6
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.6.2343-2351.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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