title: Staphylococcus aureus aconitase inactivation unexpectedly inhibits post-exponential-phase growth and enhances stationary-phase survival.
abstract: Staphylococcus aureus preferentially catabolizes glucose, generating pyruvate, which is subsequently oxidized to acetate under aerobic growth conditions. Catabolite repression of the tricarboxylic acid (TCA) cycle results in the accumulation of acetate. TCA cycle derepression coincides with exit from the exponential growth phase, the onset of acetate catabolism, and the maximal expression of secreted virulence factors. These data suggest that carbon and energy for post-exponential-phase growth and virulence factor production are derived from the catabolism of acetate mediated by the TCA cycle. To test this hypothesis, the aconitase gene was genetically inactivated in a human isolate of S. aureus, and the effects on physiology, morphology, virulence factor production, virulence for mice, and stationary-phase survival were examined. TCA cycle inactivation prevented the post-exponential growth phase catabolism of acetate, resulting in premature entry into the stationary phase. This phenotype was accompanied by a significant reduction in the production of several virulence factors and alteration in host-pathogen interaction. Unexpectedly, aconitase inactivation enhanced stationary-phase survival relative to the wild-type strain. Aconitase is an iron-sulfur cluster-containing enzyme that is highly susceptible to oxidative inactivation. We speculate that reversible loss of the iron-sulfur cluster in wild-type organisms is a survival strategy used to circumvent oxidative stress induced during host-pathogen interactions. Taken together, these data demonstrate the importance of the TCA cycle in the life cycle of this medically important pathogen.
authors.affiliation: Laboratory of Human Bacterial Pathogenesis. Rocky Mountain Microscopy Branch. Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana 59840, USA.
authors.forename: Greg A
authors.initials: GA
authors.lastname: Somerville
authors.forename: Michael S
authors.initials: MS
authors.lastname: Chaussee
authors.forename: Carrie I
authors.initials: CI
authors.lastname: Morgan
authors.forename: J Ross
authors.initials: JR
authors.lastname: Fitzgerald
authors.forename: David W
authors.initials: DW
authors.lastname: Dorward
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Reitzer
authors.forename: James M
authors.initials: JM
authors.lastname: Musser
mesh_terms: D000085:Acetates / Q000378:metabolism; D000154:Aconitate Hydratase / Q000502:physiology*; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics; D002952:Citric Acid Cycle; D005947:Glucose / Q000378:metabolism; D051379:Mice; D008812:Mice, Hairless; D020543:Proteome; D012808:Sigma Factor / Q000235:genetics; D013211:Staphylococcus aureus / Q000201:enzymology* / Q000254:growth & development* / Q000472:pathogenicity; D015534:Trans-Activators / Q000235:genetics; D014774:Virulence
chemical_list: D000085:Acetates; D000596:Amino Acids; D001426:Bacterial Proteins; D020543:Proteome; C088021:SarA protein, bacterial; C079011:SigB protein, Bacteria; D012808:Sigma Factor; D015534:Trans-Activators; D000154:Aconitate Hydratase; D005947:Glucose