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Antimicrobial Agents and Chemotherapy, January 2006, p. 298-309, Vol. 50, No. 1
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.1.298-309.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Molecular Genetic and Structural Modeling Studies of Staphylococcus aureus RNA Polymerase and the Fitness of Rifampin Resistance Genotypes in Relation to Clinical Prevalence

A. J. O'Neill,1 T. Huovinen,1 C. W. G. Fishwick,2 and I. Chopra1*

Antimicrobial Research Centre and School of Biochemistry and Microbiology, University of Leeds, Leeds LS2 9JT, United Kingdom,1 Antimicrobial Research Centre and School of Chemistry, University of Leeds, Leeds LS2 9JT, United Kingdom2

Received 26 May 2005/ Returned for modification 6 September 2005/ Accepted 3 October 2005

The adaptive and further evolutionary responses of Staphylococcus aureus to selection pressure with the antibiotic rifampin have not been explored in detail. We now present a detailed analysis of these systems. The use of rifampin for the chemotherapy of infections caused by S. aureus has resulted in the selection of mutants with alterations within the ß subunit of the target enzyme, RNA polymerase. Using a new collection of strains, we have identified numerous novel mutations in the ß subunits of both clinical and in vitro-derived resistant strains and established that additional, undefined mechanisms contribute to expression of rifampin resistance in clinical isolates of S. aureus. The fitness costs associated with rifampin resistance genotypes were found to have a significant influence on their clinical prevalence, with the most common clinical genotype (H481N, S529L) exhibiting no fitness cost in vitro. Intragenic mutations which compensate for the fitness costs associated with rifampin resistance in clinical strains of S. aureus were identified for the first time. Structural explanations for rifampin resistance and the loss of fitness were obtained by molecular modeling of mutated RNA polymerase enzymes.

* Corresponding author. Mailing address: Antimicrobial Research Centre and Division of Microbiology, University of Leeds, Leeds LS2 9JT, United Kingdom. Phone: 44 113 233 5604. Fax: 44 113 233 5638. E-mail: i.chopra{at}leeds.ac.uk.

Antimicrobial Agents and Chemotherapy, January 2006, p. 298-309, Vol. 50, No. 1
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.1.298-309.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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