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Antimicrobial Agents and Chemotherapy, April 2000, p. 814-820, Vol. 44, No. 4
Section of Infectious Diseases and Clinical
Immunology, Department of Medicine, University Hospital and Medical
Center, D-89070 Ulm,1 and Heart and
Diabetes Center NRW, D-32545 Bad
Oeynhausen,2 Germany, and Center for
Adaptation Genetics and Drug Resistance, Tufts University School of
Medicine, Boston, Massachusetts 021113
Received 9 August 1999/Returned for modification 8 November
1999/Accepted 22 December 1999
Mutations in loci other than genes for the target topoisomerases of
fluoroquinolones, gyrA and parC, may play a
role in the development of fluoroquinolone resistance in
Escherichia coli. A series of mutants with increasing
resistance to ofloxacin was obtained from an E. coli K-12
strain and five clinical isolates. First-step mutants acquired a
gyrA mutation. Second-step mutants reproducibly acquired a
phenotype of multiple antibiotic resistance (Mar) and organic solvent
tolerance and showed enhanced fluoroquinolone efflux. None of the
second-step mutants showed additional topoisomerase mutations. All
second-step mutants showed constitutive expression of marA
and/or overexpressed soxS. In some third-step mutants, fluoroquinolone efflux was further enhanced compared to that for second-step mutants, even when the mutant had acquired additional topoisomerase mutations. Attempts to circumvent the second-step Mar
mutation by induction of the mar locus with sodium
salicylate and thus to select for pure topoisomerase mutants at the
second step were not successful. At least in vitro, non-target gene
mutations accumulate in second- and third-step mutants upon exposure to a fluoroquinolone and typically include, but do not appear to be
limited to, mutations in the mar or sox
regulons with consequent increased drug efflux.
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Non-Target Gene Mutations in the Development of
Fluoroquinolone Resistance in Escherichia coli
*
Corresponding author. Mailing address: Medizinische
Universitätsklinik und Poliklinik, D-89070 Ulm, Germany. Phone:
49-731-502 4423. Fax: 49-731-502 4488. E-mail:
winfried.kern{at}medizin.uni-ulm.de.
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