title: Micafungin alters the amino acid, nucleic acid and central carbon metabolism of Candida albicans at subinhibitory concentrations: novel insights into mechanisms of action.
abstract: Echinocandins are an important class of antifungal agents in the treatment of invasive candidiasis. However, little is known about the metabolomic effects of echinocandins on Candida . We therefore performed LC-high-resolution MS (LC-HRMS)-based metabolomics profiling of the response of Candida albicans cells to increasing concentrations of micafungin to determine the metabolic response of Candida to micafungin subinhibitory injury.
  
  
  
  Isolates of C. albicans were cultured on nitrocellulose filters to mid-logarithmic phase of growth and micafungin (0-0.25 mg/L) was added. At mid-logarithmic phase, replicates were metabolically quenched. Intracellular metabolites were analysed by LC-HRMS. Changes in pool sizes of individual metabolites were analysed by Student's t -test adjusted for multiple hypothesis testing by Benjamini-Hochberg correction. Metabolites were ascribed by the Kyoto Encyclopedia of Genes and Genomes (KEGG) metabolic pathways database.
  
  
  
  Among 3446 detected metabolites, 204 were identified by comparison against pure standard or comparison against a library of mass-retention-time pairs. Fifty had significantly altered abundances in response to increasing micafungin concentrations. Pool sizes of amino acids, nucleic acids and polyamine metabolism were significantly increased at subinhibitory concentrations, while exposure to inhibitory concentrations resulted in a precipitous decrease consistent with fungicidal activity.
  
  
  
  Micafungin induces a re-routing of metabolic pathways inhibiting protein synthesis and cell replication. These results shed light on new mechanisms of action of echinocandins.
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Transplantation-Oncology Infectious Diseases Program, Weill Cornell Medicine, Cornell University, New York, NY, USA.
authors.forename: Aspasia
authors.initials: A
authors.lastname: Katragkou
authors.affiliation: University of Florida, Southeast Center for Integrated Metabolomics, Gainesville, FL, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Williams
authors.affiliation: University of Florida, Southeast Center for Integrated Metabolomics, Gainesville, FL, USA.
authors.forename: Sandi
authors.initials: S
authors.lastname: Sternberg
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Transplantation-Oncology Infectious Diseases Program, Weill Cornell Medicine, Cornell University, New York, NY, USA.
authors.forename: Dennis
authors.initials: D
authors.lastname: Pantazatos
authors.affiliation: Infectious Disease Unit, 3rd Department of Pediatrics, Faculty of Medicine, Aristotle University School of Health Sciences, Hippokration Hospital, Thessaloniki, Greece.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Roilides
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Transplantation-Oncology Infectious Diseases Program, Weill Cornell Medicine, Cornell University, New York, NY, USA.|Departments of Pediatrics, Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Walsh
mesh_terms: D000596:Amino Acids / Q000378:metabolism*; D000935:Antifungal Agents / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism*; D002177:Candidiasis / Q000382:microbiology; D058365:Candidiasis, Invasive / Q000382:microbiology; D002244:Carbon; D002853:Chromatography, Liquid; D054714:Echinocandins / Q000494:pharmacology*; D055666:Lipopeptides / Q000494:pharmacology*; D013058:Mass Spectrometry; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D055432:Metabolomics; D000077551:Micafungin; D008826:Microbial Sensitivity Tests; D009696:Nucleic Acids / Q000378:metabolism*
chemical_list: D000596:Amino Acids; D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D009696:Nucleic Acids; D002244:Carbon; D000077551:Micafungin