<p>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 <i>in vitro</i> (in the laboratory medium), and <i>in vivo</i> (in a mouse infection model), are identified in the model system of fusidic acid resistant (Fus<sup>R</sup>) <i>Salmonella</i> <i>enterica</i> serovar Typhimurium.</p><p>Fus<sup>R</sup> mutants have mutations in <i>fusA</i>, the gene that encodes translation elongation factor G (EF-G). Fus<sup>R</sup> 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 Fus<sup>R</sup> mutants <i>in vitro</i>, and <i>in vivo</i>, can be explained in part by a slow rate of protein synthesis and resulting slow growth. However, some Fus<sup>R</sup> mutants with normal rates of protein synthesis still suffer from reduced fitness <i>in vivo</i>. We observed that Fus<sup>R</sup> 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 <i>Salmonella</i>. In addition, we found that Fus<sup>R</sup> mutants have reduced amounts of heme, a co-factor of catalases and cytochromes. As a consequence of the heme defect, Fus<sup>R</sup> mutants have a reduced ability to withstand oxidative stress and a low rate of aerobic respiration.</p><p>The pleiotropic phenotypes of Fus<sup>R</sup> 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 Fus<sup>R</sup> 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.</p>
| Identifer | oai:union.ndltd.org:UPSALLA/oai:DiVA.org:uu-3761 |
| Date | January 2003 |
| Creators | Macvanin, Mirjana |
| Publisher | Uppsala University, Department of Cell and Molecular Biology, Uppsala : Acta Universitatis Upsaliensis |
| Source Sets | DiVA Archive at Upsalla University |
| Language | English |
| Detected Language | English |
| Type | Doctoral thesis, comprehensive summary, text |
| Relation | Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, 1104-232X ; 904 |
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