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Antimicrobial Agents and Chemotherapy, October 2003, p. 3061-3066, Vol. 47, No. 10
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.10.3061-3066.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Mutations in the DNA Mismatch Repair Proteins MutS and MutL of Oxazolidinone-Resistant or -Susceptible Enterococcus faecium

Rob J. Willems,1 Janetta Top,1 Derek J. Smith,2 David I. Roper,3 Sarah E. North,4 and Neil Woodford4*

Diagnostic Laboratory for Infectious Diseases and Perinatal Screening, National Institute for Public Health and the Environment, Bilthoven, The Netherlands,1 Structural Biology Laboratory, University of York, York,2 Protein Structure Research Group, Department of Biological Sciences, University of Warwick, Coventry,3 Antibiotic Resistance Monitoring and Reference Laboratory, Specialist and Reference Microbiology Division, Health Protection Agency—Colindale, London, United Kingdom4

Received 27 May 2003/ Returned for modification 30 June 2003/ Accepted 2 July 2003

Mutations in mutS and mutL, which encode DNA mismatch repair (MMR) proteins, can confer hypermutator phenotypes and may facilitate the emergence of mutational antibiotic resistance in bacteria. Linezolid-resistant enterococci (LRE) rarely emerge during therapy and contain mutations in 23S rRNA genes. As enterococci with defective MMR could be prone to the development of oxazolidinone resistance mutations, we investigated 13 clinical isolates of Enterococcus faecium, including 2 LRE, for mutations in mutSL. A 4,944-bp fragment spanning mutSL was sequenced from two pairs of linezolid-resistant (MICs, 64 µg/ml) and linezolid-susceptible (MICs, 2 µg/ml) E. faecium isolates (one pair from Austria and one pair from the United Kingdom) identical by pulsed-field gel electrophoresis. The pairs represented distinct strains in which linezolid resistance had emerged during therapy. The MutSL peptides of all four isolates had amino acid substitutions compared with the sequence of E. faecium strain DO (used for genome sequencing). These were Val352Ile (one pair of isolates only) and Met628Leu in MutS and Leu387Pro, Tyr406Phe, Thr415Ser, Phe427Leu, and Phe565Ile in MutL. The significance of these changes remains unknown; these isolates did not show a demonstrable hypermutator phenotype. The same substitutions were found in two of nine geographically diverse linezolid-susceptible enterococcal isolates; the other seven isolates had MutSL sequences identical to that of strain DO. Multilocus sequence typing revealed that all isolates with alternate MutSL peptides belonged to a distinct lineage of a prevalent E. faecium clonal complex, designated CC17. Further studies are needed to investigate the prevalence of these MutSL mutations and their possible roles in the emergence of E. faecium strains resistant to oxazolidinones and other antibiotic classes.

* Corresponding author. Mailing address: ARMRL, SRMD, Health Protection Agency—Colindale, 61 Colindale Ave., London NW9 5HT, United Kingdom. Phone: 44-20-8200-4400, ext. 4255. Fax: 44-20-8358-3292. E-mail: neil.woodford{at}hpa.org.uk.

Antimicrobial Agents and Chemotherapy, October 2003, p. 3061-3066, Vol. 47, No. 10
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.10.3061-3066.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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