title: Compensatory adaptation to the loss of biological fitness associated with acquisition of fusidic acid resistance in Staphylococcus aureus.
abstract: 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 substitutions P406L and H457Y are associated with a marked impairment of the biological fitness of S. aureus. In particular, strains producing EF-G derivatives with these mutations showed reduced growth, decreased plasma coagulase activity, and an impaired capability to compete with the isogenic wild-type strain. Second-site mutations within EF-G, such as A67T and S416F, that have been encountered in clinical fusidic acid-resistant isolates containing the amino acid exchanges P406L and H457Y, respectively, were shown not to contribute to resistance. Furthermore, the substitution A67T had no impact on the biological fitness in vitro. 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.
authors.affiliation: Institut für Medizinische Mikrobiologie, Klinikum der Johann Wolfgang Goethe-Universität, Paul-Ehrlich-Strasse 40, 60596 Frankfurt am Main, Germany. s.besier@em.uni-frankfurt.de
authors.forename: Silke
authors.initials: S
authors.lastname: Besier
authors.forename: Albrecht
authors.initials: A
authors.lastname: Ludwig
authors.forename: Volker
authors.initials: V
authors.lastname: Brade
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Wichelhaus
mesh_terms: D019943:Amino Acid Substitution; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D003030:Coagulase / Q000378:metabolism; D024881:Drug Resistance, Bacterial; D005672:Fusidic Acid / Q000494:pharmacology*; D006801:Humans; D020653:Peptide Elongation Factor G / Q000235:genetics* / Q000378:metabolism; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development*
chemical_list: D000900:Anti-Bacterial Agents; D003030:Coagulase; D020653:Peptide Elongation Factor G; D005672:Fusidic Acid