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Antimicrobial Agents and Chemotherapy, April 2004, p. 1289-1294, Vol. 48, No. 4
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.4.1289-1294.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Effect of rpoB Mutations Conferring Rifampin Resistance on Fitness of Mycobacterium tuberculosis

Deneke H. Mariam,1,2 Yohannes Mengistu,3 Sven E. Hoffner,1 and Dan I. Andersson1,4*

Department of Bacteriology, Swedish Institute for Infectious Disease Control, S-171 82 Solna,1 Microbiology and Tumour Biology Center, Karolinska Institute, S-171 77 Solna, Sweden,4 Armaeur Hansen Research Institute,2 Department of Microbiology and Parasitology, Faculty of Medicine, Addis Ababa University, Addis Ababa, Ethiopia3

Received 27 October 2003/ Returned for modification 15 December 2003/ Accepted 29 December 2003

Rifampin is a major drug used in the treatment of tuberculosis infections, and increasing rifampin resistance represents a worldwide clinical problem. Resistance to rifampin is caused by mutations in the rpoB gene, encoding the ß-subunit of RNA polymerase. We examined the effect of three different rpoB mutations on the fitness of Mycobacterium tuberculosis. Rifampin-resistant mutants were isolated from a virulent clinical isolate of M. tuberculosis (strain Harlingen) in vitro at a mutation frequency of 2.3 x 10-8. Mutations in the rpoB gene were identified, and the growth rates of three defined mutants were measured by competition with the susceptible parent strain in laboratory medium and by single cultures in a macrophage cell line and in laboratory medium. All of the mutants showed a decreased growth rate in the three assays. The relative fitness of the mutants varied between 0.29 and 0.96 (that of the susceptible strain was set to 1.0) depending on the specific mutant and assay system. Unexpectedly, the relative fitness ranking of the mutants differed between the different assays. In conclusion, rifampin resistance is associated with a cost that is conditional.

* Corresponding author. Mailing address: Department of Bacteriology, Swedish Institute for Infectious Disease Control, S-171 82 Solna, Sweden. Phone: 46 8 4572432. Fax: 46 8 301797. E-mail: Dan.Andersson{at}smi.ki.se.

Antimicrobial Agents and Chemotherapy, April 2004, p. 1289-1294, Vol. 48, No. 4
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.4.1289-1294.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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