title: Central Role of the Trehalose Biosynthesis Pathway in the Pathogenesis of Human Fungal Infections: Opportunities and Challenges for Therapeutic Development.
abstract: Invasive fungal infections cause significant morbidity and mortality in part due to a limited antifungal drug arsenal. One therapeutic challenge faced by clinicians is the significant host toxicity associated with antifungal drugs. Another challenge is the fungistatic mechanism of action of some drugs. Consequently, the identification of fungus-specific drug targets essential for fitnessin vivoremains a significant goal of medical mycology research. The trehalose biosynthetic pathway is found in a wide variety of organisms, including human-pathogenic fungi, but not in humans. Genes encoding proteins involved in trehalose biosynthesis are mechanistically linked to the metabolism, cell wall homeostasis, stress responses, and virulence ofCandida albicans,Cryptococcus neoformans, andAspergillus fumigatus. While there are a number of pathways for trehalose production across the tree of life, the TPS/TPP (trehalose-6-phosphate synthase/trehalose-6-phosphate phosphatase) pathway is the canonical pathway found in human-pathogenic fungi. Importantly, data suggest that proteins involved in trehalose biosynthesis play other critical roles in fungal metabolism andin vivofitness that remain to be fully elucidated. By further defining the biology and functions of trehalose and its biosynthetic pathway components in pathogenic fungi, an opportunity exists to leverage this pathway as a potent antifungal drug target. The goal of this review is to cover the known roles of this important molecule and its associated biosynthesis-encoding genes in the human-pathogenic fungi studied to date and to employ these data to critically assess the opportunities and challenges facing development of this pathway as a therapeutic target.
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA.
authors.forename: Arsa
authors.initials: A
authors.lastname: Thammahong
authors.affiliation: Department of Microbiology, Faculty of Medicine, Srinakharinwirot University, Bangkok, Thailand.
authors.forename: Srisombat
authors.initials: S
authors.lastname: Puttikamonkul
authors.affiliation: Division of Infectious Diseases, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Perfect
authors.affiliation: Department of Biochemistry, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Brennan
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA Robert.A.Cramer.JR@dartmouth.edu.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Cramer
mesh_terms: D000935:Antifungal Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D001232:Aspergillus fumigatus / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity; D053898:Biosynthetic Pathways / Q000235:genetics; D002176:Candida albicans / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity; D003455:Cryptococcus neoformans / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity; D055808:Drug Discovery; D005658:Fungi / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D005964:Glucosyltransferases / Q000235:genetics; D054884:Host-Pathogen Interactions; D006801:Humans; D000072742:Invasive Fungal Infections / Q000382:microbiology* / Q000628:therapy*; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics; D014199:Trehalose / Q000096:biosynthesis*; D014774:Virulence; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D000935:Antifungal Agents; D037521:Virulence Factors; D014199:Trehalose; D005964:Glucosyltransferases; C023180:trehalose-6-phosphate synthase; C023178:trehalose-phosphatase; D010744:Phosphoric Monoester Hydrolases
keywords: antifungal agents; antifungal therapy; carbon metabolism; cell wall; fungal pathogenesis; fungal virulence; trehalose