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The Physiological Cost of Antibiotic Resistance
Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology.
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Becoming antibiotic resistant is often associated with fitness costs for the resistant bacteria. This is seen as a loss of competitiveness against the antibiotic-sensitive wild-type in an antibiotic-free environment. In this study, the physiological alterations associated with fitness cost of antibiotic resistance in vitro (in the laboratory medium), and in vivo (in a mouse infection model), are identified in the model system of fusidic acid resistant (FusR) Salmonella enterica serovar Typhimurium.

FusR mutants have mutations in fusA, the gene that encodes translation elongation factor G (EF-G). FusR EF-G has a slow rate of regeneration of active EF-G·GTP off the ribosome, resulting in a slow rate of protein synthesis. The low fitness of FusR mutants in vitro, and in vivo, can be explained in part by a slow rate of protein synthesis and resulting slow growth. However, some FusR mutants with normal rates of protein synthesis still suffer from reduced fitness in vivo. We observed that FusR mutants have perturbed levels of the global regulatory molecule ppGpp. One consequence of this is an inefficient induction of RpoS, a regulator of general stress reponse and an important virulence factor for Salmonella. In addition, we found that FusR mutants have reduced amounts of heme, a co-factor of catalases and cytochromes. As a consequence of the heme defect, FusR mutants have a reduced ability to withstand oxidative stress and a low rate of aerobic respiration.

The pleiotropic phenotypes of FusR mutants suggest that antibiotic resistance can be associated with broad changes in bacterial physiology. Knowledge of physiological alterations that reduce the fitness of antibiotic-resistant mutants can be useful in identifying novel targets for antimicrobial agents. Drugs that alter the levels of global transcriptional regulators such as ppGpp or RpoS deserve attention as potential antimicrobial agents. Finally, the observation that FusR mutants have increased sensitivity to several unrelated classes of antibiotics suggests that the identification of physiological cost of resistance can help in optimizing treatment of resistant bacterial populations.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2003. , p. 63
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1104-232X ; 904
Keywords [en]
Microbiology, fusidic acid, fitness cost, protein synthesis, EF-G, ppGpp, RpoS, oxidative stress, heme
Keywords [sv]
Mikrobiologi
National Category
Microbiology in the medical area
Identifiers
URN: urn:nbn:se:uu:diva-3761ISBN: 91-554-5794-0 (print)OAI: oai:DiVA.org:uu-3761DiVA, id: diva2:163601
Public defence
2003-12-12, C8:305, Biomedical Center, Uppsala, 13:00
Opponent
Supervisors
Available from: 2003-11-21 Created: 2003-11-21 Last updated: 2022-03-11Bibliographically approved
List of papers
1. Fusidic acid-resistant EF-G perturbs the accumulation of ppGpp
Open this publication in new window or tab >>Fusidic acid-resistant EF-G perturbs the accumulation of ppGpp
2000 In: Molecular Microbiology, Vol. 37, no 1, p. 98-107Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-91024 (URN)
Available from: 2003-11-21 Created: 2003-11-21Bibliographically approved
2. Fusidic acid-resistant mutants of Salmonella enterica serovar Typhimurium with low fitness in vivo are defective in RpoS induction
Open this publication in new window or tab >>Fusidic acid-resistant mutants of Salmonella enterica serovar Typhimurium with low fitness in vivo are defective in RpoS induction
Show others...
2003 In: Antimicrobial Agents and Chemotherapy, Vol. 47, no 12Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-91025 (URN)
Available from: 2003-11-21 Created: 2003-11-21Bibliographically approved
3. Reduced levels of heme and respiration rate in elongation factor G mutants of Salmonella enterica serovar Typhimurium
Open this publication in new window or tab >>Reduced levels of heme and respiration rate in elongation factor G mutants of Salmonella enterica serovar Typhimurium
Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-91026 (URN)
Available from: 2003-11-21 Created: 2003-11-21 Last updated: 2010-01-13Bibliographically approved
4. Hypersensitivity of fusidic acid-resistant mutants of Salmonella enterica serovar Typhimurium to several classes of antibiotics
Open this publication in new window or tab >>Hypersensitivity of fusidic acid-resistant mutants of Salmonella enterica serovar Typhimurium to several classes of antibiotics
Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-91027 (URN)
Available from: 2003-11-21 Created: 2003-11-21 Last updated: 2010-01-13Bibliographically approved

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