title: Compensatory mutations in agrC partly restore fitness in vitro to peptide deformylase inhibitor-resistant Staphylococcus aureus.
abstract: OBJECTIVE
  To determine how the fitness cost of deformylase inhibitor resistance conferred by fmt mutations can be genetically compensated.
  
  
  METHODS
  Resistant mutants were isolated and characterized with regard to their growth rates in vitro and in neutropenic mice, MIC and DNA sequence. Faster-growing compensated mutants were isolated by serial passage in culture medium, and for a subset of the resistant and compensated mutants whole-genome sequencing was performed.
  
  
  RESULTS
  Staphylococcus aureus mutants resistant to the peptide deformylase inhibitor actinonin had mutations in the fmt gene that conferred high-level actinonin resistance and reduced bacterial growth rate. Compensated mutants that remained fully resistant to actinonin and showed increased growth rates appeared within 30-60 generations of growth. Whole-genome sequencing and localized DNA sequencing of mutated candidate genes showed that alterations in the gene agrC were present in the majority of compensated strains. Resistant and compensated mutants grew at similar rates as the wild-type in a mouse thigh infection model.
  
  
  CONCLUSIONS
  Resistance to deformylase inhibitors due to fmt mutations reduces bacterial growth rates, but these costs can be reduced by mutations in the agrC gene. Mutants defective in fmt (with or without compensatory agrC mutations) grew well in an animal model, implying that they can also cause infection in a host.
authors.affiliation: Department of Medical Biochemistry and Microbiology,  Uppsala University, Uppsala,  Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Zorzet
authors.forename: Jytte Mark
authors.initials: JM
authors.lastname: Andersen
authors.forename: Annika I
authors.initials: AI
authors.lastname: Nilsson
authors.forename: Niels Frimodt
authors.initials: NF
authors.lastname: Møller
authors.forename: Dan I
authors.initials: DI
authors.lastname: Andersson
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics*; D003470:Culture Media / Q000737:chemistry; D004195:Disease Models, Animal; D024881:Drug Resistance, Bacterial; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D051379:Mice; D008826:Microbial Sensitivity Tests; D011494:Protein Kinases / Q000235:genetics*; D012692:Serial Passage; D013203:Staphylococcal Infections / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000472:pathogenicity / Q000502:physiology; D013489:Suppression, Genetic; D014774:Virulence
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D003470:Culture Media; D004791:Enzyme Inhibitors; D011494:Protein Kinases; C531166:AgrC protein, Staphylococcus; D000581:Amidohydrolases; C084507:peptide deformylase