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Antimicrobial Agents and Chemotherapy, December 2003, p. 3743-3749, Vol. 47, No. 12
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.12.3743-3749.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Fusidic Acid-Resistant Mutants of Salmonella enterica Serovar Typhimurium with Low Fitness In Vivo Are Defective in RpoS Induction

Mirjana Macvanin,1 Johanna Björkman,2 Sofia Eriksson,3 Mikael Rhen,3 Dan I. Andersson,2 and Diarmaid Hughes1*

Department of Cell and Molecular Biology, The Biomedical Center, Uppsala University, S-751 24 Uppsala,1 Department of Bacteriology, Swedish Institute for Infectious Disease Control, S-171 82 Solna,2 Microbiology and Tumour Biology Center, The Karolinska Institute, S-171 77 Stockholm, Sweden3

Received 4 July 2003/ Returned for modification 24 August 2003/ Accepted 3 September 2003

Mutants of Salmonella enterica serovar Typhimurium resistant to fusidic acid (Fusr) have mutations in fusA, the gene encoding translation elongation factor G (EF-G). Most Fusr mutants have reduced fitness in vitro and in vivo, in part explained by mutant EF-G slowing the rate of protein synthesis and growth. However, some Fusr mutants with normal rates of protein synthesis still suffer from reduced fitness in vivo. As shown here, Fusr mutants could be similarly ranked in their relative fitness in mouse infection models, in a macrophage infection model, in their relative hypersensitivity to hydrogen peroxide in vivo and in vitro, and in the amount of RpoS production induced upon entry into the stationary phase. We identify a reduced ability to induce production of RpoS ({sigma}s) as a defect associated with Fusr strains. Because RpoS is a regulator of the general stress response, and an important virulence factor in Salmonella, an inability to produce RpoS in appropriate amounts can explain the low fitness of Fusr strains in vivo. The unfit Fusr mutants also produce reduced levels of the regulatory molecule ppGpp in response to starvation. Because ppGpp is a positive regulator of RpoS production, we suggest that a possible cause of the reduced levels of RpoS is the reduction in ppGpp production associated with mutant EF-G. The low fitness of Fusr mutants in vivo suggests that drugs that can alter the levels of global regulators of gene expression deserve attention as potential antimicrobial agents.

* Corresponding author. Mailing address: Department of Cell and Molecular Biology, Box 596, The Biomedical Center, Uppsala University, S-751 24 Uppsala, Sweden. Phone: 46-18-4714354. Fax: 46-18-530396. E-mail: diarmaid.hughes{at}icm.uu.se.

Antimicrobial Agents and Chemotherapy, December 2003, p. 3743-3749, Vol. 47, No. 12
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.12.3743-3749.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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