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Compensatory adaptation to the loss of biological fitness associated with the acquisition of fusidic acid resistance in Staphylococcus aureus

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Silke Besier, Albrecht Ludwig, Volker Brade, Thomas A. Wichelhaus

Klinikum der J W. Goethe-Universität
Institut für Medizinische Mikrobiologie
Paul-Ehrlich-Straße 40
D - 60596 Frankfurt / Main
Fon: +49 / 69 / 6301 - 6438
Fax: +49 / 69 / 6301 - 5767
eMail: wichelhaus@em.uni-frankfurt.de

Recent studies have shown that individual amino acid exchanges within elongation factor G (EF-G) cause fusidic acid resistance in Staphylococcus aureus. The data from the present study illustrate that the fusidic acid resistance-mediating amino acid substitution H457Y perturbs EF-G functionality and is associated with a marked impairment of the biological fitness of S. aureus. These complex costs were shown to affect the normal physiological process in the cell, as documented by reduced growth, impaired expression of the virulence factor plasmacoagulase, and poor ability to compete with the isogenic strain expressing wild-type EF-G. A Second-site mutation within EF-G, i.e. S416F, which has been encountered in clinical fusidic acid-resistant isolates containing the amino acid exchange H457Y, was shown not to contribute to resistance. The exchange S416F, however, was found to function as a fitness-compensating mutation in S. aureus carrying the substitution H457Y in EF-G. In conclusion, the data presented in this report provide evidence at the molecular level that the deleterious effects of fusidic acid resistance-mediating exchanges within EF-G of S. aureus can be reduced considerably by specific compensating mutations in this target protein. This compensatory adaptation most likely plays a significant role in the stabilization of resistant bacteria within a given population. Hence, bacteria often do pay a metabolic price, such as reduced growth rate, reduced invasiveness, or loss of virulence for the acquisition of drug resistance in the short term, but their adaptation to the physiological cost is likely to foster stable maintenance of resistance in the long term. Extrapolation of these findings make it tempting to speculate that resistance will never disappear completely because there is no evolutionary disadvantage to being resistant once adaptation has taken place.