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Antimicrobial Agents and Chemotherapy, September 2007, p. 3225-3229, Vol. 51, No. 9
0066-4804/07/$08.00+0     doi:10.1128/AAC.00336-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Identifying Mutator Phenotypes among Fluoroquinolone-Resistant Strains of Streptococcus pneumoniae Using Fluctuation Analysis

Carolyn V. Gould,^1, Paul D. Sniegowski,² Mikhail Shchepetov,³ Joshua P. Metlay,^1,4 and Jeffrey N. Weiser^3*

Departments of Microbiology,³ Medicine,¹ Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104,² Veteran's Administration Medical Center, Philadelphia, Pennsylvania, 19104⁴

Received 12 March 2007/ Returned for modification 6 April 2007/ Accepted 3 July 2007

The occurrence of mutator phenotypes among laboratory-generated and clinical levofloxacin-resistant strains of Streptococcus pneumoniae was determined using fluctuation analysis. The in vitro selection for levofloxacin-resistant mutants of strain D39, each with point mutations in both gyrA and parC or parE, was not associated with a significant change in the mutation rate. Two of eight clinical isolates resistant to levofloxacin (MIC, >8 µg/ml) had estimated mutation rates of 1.2 x 10^–7 and 9.4 x 10^–8 mutations per cell division, indicating potential mutator phenotypes, compared to strain D39, which had an estimated mutation rate of 1.4 x 10^–8 mutations per cell division. The levofloxacin-resistant isolates with the highest mutation rates showed evidence of dysfunctional mismatch repair and contained missense mutations in mut genes at otherwise highly conserved sites. The association of hypermutability in levofloxacin-resistant S. pneumoniae clinical isolates with mutations in DNA mismatch repair genes provides further evidence that mismatch repair mutants may have a selective advantage in the setting of antibiotic pressure, facilitating the development of further antibiotic resistance.

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* Corresponding author. Mailing address: 402A Johnson Pavilion, Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104-6076. Phone: (215) 573-3511. Fax: (215) 898-9557. E-mail: weiser{at}mail.med.upenn.edu

Published ahead of print on 30 July 2007.

Present address: Centers for Disease Control and Prevention, 1600 Clifton Rd. NE, Mailstop A-35, Atlanta, GA 30333.

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Antimicrobial Agents and Chemotherapy, September 2007, p. 3225-3229, Vol. 51, No. 9
0066-4804/07/$08.00+0     doi:10.1128/AAC.00336-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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