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Understanding the mechanisms of how bacteria become tolerant toward antibiotics during clinical therapy is a very important object. In a previous study, we showed that increased daptomycin (DAP) tolerance ofStaphylococcus aureus was due to a point mutation inpitA (inorganic phosphate transporter) that led to intracellular accumulation of both inorganic phosphate (Pi ) and polyphosphate (polyP). DAP tolerance in thepitA6 mutant differs from classical resistance mechanisms since there is no increase in the MIC. In this follow-up study, we demonstrate that DAP tolerance in thepitA6 mutant is not triggered by the accumulation of polyP. Transcriptome analysis revealed that 234 genes were at least 2.0-fold differentially expressed in the mutant. Particularly, genes involved in protein biosynthesis, carbohydrate and lipid metabolism, and replication and maintenance of DNA were downregulated. However, the most important change was the upregulation of thedlt operon, which is induced by the accumulation of intracellular Pi . The GraXRS system, known as an activator of thedlt operon (d -alanylation of teichoic acids) and of themprF gene (multiple peptide resistance factor), is not involved in DAP tolerance of thepitA6 mutant. In conclusion, DAP tolerance of thepitA6 mutant is due to an upregulation of thedlt operon, triggered directly or indirectly by the accumulation of Pi .

Daptomycin Tolerance in the Staphylococcus aureus pitA6 Mutant Is Due to Upregulation of the dlt Operon