Synthesis and Deformylation of Staphylococcus aureus δ-Toxin Are Linked to Tricarboxylic Acid Cycle Activity

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Abstract
In bacteria, translation initiates with formyl-methionine; however, the N-terminal formyl group is usually removed by peptide deformylase, an enzymatic activity requiring iron. Staphylococcus aureus δ-toxin is a 26-amino-acid polypeptide secreted predominantly with a formylated N-terminal methionine, which led us to investigate regulation of δ-toxin deformylation. We observed that during exponential and early postexponential growth, δ-toxin accumulated in the culture medium in formylated and deformylated forms. In contrast, only formylated δ-toxin accumulated after the early postexponential phase. The transition from producing both species of δ-toxin to producing only formyl-methionine-containing δ-toxin coincided with increased tricarboxylic acid (TCA) cycle activity. The TCA cycle contains several iron-requiring enzymes, which led us to hypothesize that TCA cycle induction depletes the iron in the culture medium, thereby inhibiting peptide deformylase activity. As expected, S. aureus depletes the iron in the culture medium between the postexponential and stationary phases of growth. Inhibition of δ-toxin deformylation was relieved by TCA cycle inactivation or by addition of supplemental iron to the culture medium. Of interest, peptides containing formyl-methionine are potent chemoattractants for neutrophils, suggesting that δ-toxin deformylation may have functional consequences. We found neutrophil chemotactic activity only with formylated δ-toxin. The S. aureus TCA cycle is derepressed upon depletion of rapidly catabolizable carbon sources; this coincides with the transition to producing only formylated δ-toxin and results in an increased inflammatory response. The proinflammatory response should increase host cell damage and result in the release of nutrients. Taken together, these results establish that there is an important linkage between bacterial metabolism and pathogenesis.