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Antimicrobial Agents and Chemotherapy, October 2003, p. 3222-3232, Vol. 47, No. 10
0066-4804/03/$08.00+0 DOI: 10.1128/AAC.47.10.3222-3232.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.
Mutation Rate and Evolution of Fluoroquinolone Resistance in Escherichia coli Isolates from Patients with Urinary Tract Infections
Patricia Komp Lindgren, Åsa Karlsson, and Diarmaid Hughes*
Department of Cell and Molecular Biology, Microbiology Programme, Biomedical Center, Uppsala University, S-751 24 Uppsala, Sweden
Received 16 May 2003/ Returned for modification 8 July 2003/ Accepted 11 July 2003
Escherichia coli strains from patients with uncomplicated urinary tract infections were examined by DNA sequencing for fluoroquinolone resistance-associated mutations in six genes: gyrA, gyrB, parC, parE, marOR, and acrR. The 54 strains analyzed had a susceptibility range distributed across 15 dilutions of the fluoroquinolone MICs. There was a correlation between the fluoroquinolone MIC and the number of resistance mutations that a strain carried, with resistant strains having mutations in two to five of these genes. Most resistant strains carried two mutations in gyrA and one mutation in parC. In addition, many resistant strains had mutations in parE, marOR, and/or acrR. No (resistance) mutation was found in gyrB. Thus, the evolution of fluoroquinolone resistance involves the accumulation of multiple mutations in several genes. The spontaneous mutation rate in these clinical strains varied by 2 orders of magnitude. A high mutation rate correlated strongly with a clinical resistance phenotype. This correlation suggests that an increased general mutation rate may play a significant role in the development of high-level resistance to fluoroquinolones by increasing the rate of accumulation of rare new mutations.