title: Daptomycin Tolerance in the Staphylococcus aureus pitA6 Mutant Is Due to Upregulation of the dlt Operon.
abstract: 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 of Staphylococcus aureus was due to a point mutation in pitA (inorganic phosphate transporter) that led to intracellular accumulation of both inorganic phosphate (Pi) and polyphosphate (polyP). DAP tolerance in the pitA6 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 the pitA6 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 the dlt operon, which is induced by the accumulation of intracellular Pi The GraXRS system, known as an activator of the dlt operon (d-alanylation of teichoic acids) and of the mprF gene (multiple peptide resistance factor), is not involved in DAP tolerance of the pitA6 mutant. In conclusion, DAP tolerance of the pitA6 mutant is due to an upregulation of the dlt operon, triggered directly or indirectly by the accumulation of Pi.
authors.affiliation: Microbial Genetics, Interfaculty Institute of Microbiology and Infection Medicine, University of Tuebingen, Tübingen, Germany.
authors.forename: Lukas
authors.initials: L
authors.lastname: Mechler
authors.affiliation: Genomic Research Laboratory, University Hospitals of Geneva and University of Geneva, Geneva, Switzerland.
authors.forename: Eve-Julie
authors.initials: EJ
authors.lastname: Bonetti
authors.affiliation: Microbial Genetics, Interfaculty Institute of Microbiology and Infection Medicine, University of Tuebingen, Tübingen, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Reichert
authors.affiliation: Max Planck Institute for Developmental Biology, Tübingen, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Flötenmeyer
authors.affiliation: Genomic Research Laboratory, University Hospitals of Geneva and University of Geneva, Geneva, Switzerland.
authors.forename: Jacques
authors.initials: J
authors.lastname: Schrenzel
authors.affiliation: Microbial Genetics, Interfaculty Institute of Microbiology and Infection Medicine, University of Tuebingen, Tübingen, Germany Research Office, Paracelsus Medical University, Nürnberg, Germany.
authors.forename: Ralph
authors.initials: R
authors.lastname: Bertram
authors.affiliation: Genomic Research Laboratory, University Hospitals of Geneva and University of Geneva, Geneva, Switzerland.
authors.forename: Patrice
authors.initials: P
authors.lastname: François
authors.affiliation: Microbial Genetics, Interfaculty Institute of Microbiology and Infection Medicine, University of Tuebingen, Tübingen, Germany friedrich.goetz@uni-tuebingen.de.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Götz
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D017576:Daptomycin / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D009876:Operon / Q000235:genetics*; D017354:Point Mutation / Q000235:genetics; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D013682:Teichoic Acids / Q000378:metabolism; D059467:Transcriptome / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D013682:Teichoic Acids; D017576:Daptomycin