title: Integrating Candida albicans metabolism with biofilm heterogeneity by transcriptome mapping.
abstract: Candida albicans biofilm formation is an important virulence factor in the pathogenesis of disease, a characteristic which has been shown to be heterogeneous in clinical isolates. Using an unbiased computational approach we investigated the central metabolic pathways driving biofilm heterogeneity. Transcripts from high (HBF) and low (LBF) biofilm forming isolates were analysed by RNA sequencing, with 6312 genes identified to be expressed in these two phenotypes. With a dedicated computational approach we identified and validated a significantly differentially expressed subnetwork of genes associated with these biofilm phenotypes. Our analysis revealed amino acid metabolism, such as arginine, proline, aspartate and glutamate metabolism, were predominantly upregulated in the HBF phenotype. On the contrary, purine, starch and sucrose metabolism was generally upregulated in the LBF phenotype. The aspartate aminotransferase gene AAT1 was found to be a common member of these amino acid pathways and significantly upregulated in the HBF phenotype. Pharmacological inhibition of AAT1 enzyme activity significantly reduced biofilm formation in a dose-dependent manner. Collectively, these findings provide evidence that biofilm phenotype is associated with differential regulation of metabolic pathways. Understanding and targeting such pathways, such as amino acid metabolism, is potentially useful for developing diagnostics and new antifungals to treat biofilm-based infections.
authors.affiliation: School of Medicine, College of Medical, Veterinary and Life Sciences (MVLS), University of Glasgow, UK.
authors.forename: Ranjith
authors.initials: R
authors.lastname: Rajendran
authors.affiliation: Department of Preventive Dentistry, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and VU University Amsterdam, The Netherlands.|Centre for Integrative Bioinformatics VU (IBIVU), VU University Amsterdam, The Netherlands.
authors.forename: Ali
authors.initials: A
authors.lastname: May
authors.affiliation: School of Medicine, College of Medical, Veterinary and Life Sciences (MVLS), University of Glasgow, UK.
authors.forename: Leighann
authors.initials: L
authors.lastname: Sherry
authors.affiliation: School of Medicine, College of Medical, Veterinary and Life Sciences (MVLS), University of Glasgow, UK.|Institute of Healthcare Associated Infection, School of Health, Nursing and Midwifery, University of the West of Scotland, UK.
authors.forename: Ryan
authors.initials: R
authors.lastname: Kean
authors.affiliation: Institute of Healthcare Associated Infection, School of Health, Nursing and Midwifery, University of the West of Scotland, UK.
authors.forename: Craig
authors.initials: C
authors.lastname: Williams
authors.affiliation: Microbiology Department, Glasgow Royal Infirmary, Glasgow, UK.
authors.forename: Brian L
authors.initials: BL
authors.lastname: Jones
authors.affiliation: Polyomics Facility, MVLS, University of Glasgow, UK.
authors.forename: Karl V
authors.initials: KV
authors.lastname: Burgess
authors.affiliation: Centre for Integrative Bioinformatics VU (IBIVU), VU University Amsterdam, The Netherlands.
authors.forename: Jaap
authors.initials: J
authors.lastname: Heringa
authors.affiliation: Centre for Integrative Bioinformatics VU (IBIVU), VU University Amsterdam, The Netherlands.
authors.forename: Sanne
authors.initials: S
authors.lastname: Abeln
authors.affiliation: Department of Preventive Dentistry, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and VU University Amsterdam, The Netherlands.
authors.forename: Bernd W
authors.initials: BW
authors.lastname: Brandt
authors.affiliation: Aberdeen Fungal Group, MRC Centre for Medical Mycology, University of Aberdeen, UK.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Munro
authors.affiliation: School of Medicine, College of Medical, Veterinary and Life Sciences (MVLS), University of Glasgow, UK.
authors.forename: Gordon
authors.initials: G
authors.lastname: Ramage
mesh_terms: D000465:Algorithms; D000935:Antifungal Agents / Q000494:pharmacology; D018441:Biofilms / Q000187:drug effects*; D002176:Candida albicans / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D005800:Genes, Fungal; D010641:Phenotype; D017422:Sequence Analysis, DNA; D017423:Sequence Analysis, RNA; D059467:Transcriptome
chemical_list: D000935:Antifungal Agents