title: Metabolic and transcriptional activities of Staphylococcus aureus challenged with high-doses of daptomycin.
abstract: Treatment of stationary growth phase Staphylococcus aureus SA113 with 100-fold of the MIC of the lipopeptide antibiotic daptomycin leaves alive a small fraction of drug tolerant albeit genetically susceptible bacteria. This study shows that cells of this subpopulation exhibit active metabolism even hours after the onset of the drug challenge. Isotopologue profiling using fully (13)C-labeled glucose revealed de novo biosynthesis of the amino acids Ala, Asp, Glu, Ser, Gly and His. The isotopologue composition in Asp and Glu suggested an increased activity of the TCA cycle under daptomycin treatment compared to unaffected stationary growth phase cells. Microarray analysis showed differential expression of specific genes 10 min and 3 h after addition of the drug. Besides factors involved in drug response, a number of metabolic genes appear to shape the signature of daptomycin-tolerant S. aureus cells. These observations will be useful toward the development of new strategies against persisters and related forms of bacterial cells with downshifted physiology.
authors: Interfakultäres Institut für Mikrobiologie und Infektionsmedizin, Lehrbereich Mikrobielle Genetik, Waldhäuser Str. 70/8, Eberhard Karls Universität Tübingen, 72076 Tübingen, Germany.
authors: Sabrina
authors: S
authors: Lechner
authors: Interfakultäres Institut für Mikrobiologie und Infektionsmedizin, Lehrbereich Mikrobielle Genetik, Waldhäuser Str. 70/8, Eberhard Karls Universität Tübingen, 72076 Tübingen, Germany.
authors: Marcel
authors: M
authors: Prax
authors: Lehrstuhl für Biochemie, Technische Universität München, Lichtenbergstr. 4, 85747 Garching, Germany.
authors: Birgit
authors: B
authors: Lange
authors: Lehrstuhl für Biochemie, Technische Universität München, Lichtenbergstr. 4, 85747 Garching, Germany.
authors: Claudia
authors: C
authors: Huber
authors: Lehrstuhl für Biochemie, Technische Universität München, Lichtenbergstr. 4, 85747 Garching, Germany.
authors: Wolfgang
authors: W
authors: Eisenreich
authors: Zentrum für Bioinformatik, Forschungsgruppe Integrative Transkriptomik, Eberhard Karls Universität Tübingen, Sand 14, 72076 Tübingen, Germany.
authors: Alexander
authors: A
authors: Herbig
authors: Zentrum für Bioinformatik, Forschungsgruppe Integrative Transkriptomik, Eberhard Karls Universität Tübingen, Sand 14, 72076 Tübingen, Germany.
authors: Kay
authors: K
authors: Nieselt
authors: Interfakultäres Institut für Mikrobiologie und Infektionsmedizin, Lehrbereich Mikrobielle Genetik, Waldhäuser Str. 70/8, Eberhard Karls Universität Tübingen, 72076 Tübingen, Germany. Electronic address: ralph.bertram@uni-tuebingen.de.
authors: Ralph
authors: R
authors: Bertram
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002952:Citric Acid Cycle / Q000235:genetics; D017576:Daptomycin / Q000494:pharmacology*; D004361:Drug Tolerance; D020869:Gene Expression Profiling; D005947:Glucose / Q000378:metabolism; D007553:Isotope Labeling; D046228:Microarray Analysis; D014176:Protein Biosynthesis; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological
chemical_list: D000900:Anti-Bacterial Agents; D005947:Glucose; D017576:Daptomycin
keywords: Daptomycin; Drug tolerance; Persisters; Staphylococcus aureus