title: Trehalose pathway as an antifungal target.
abstract: With an increasing immunocompromised population which is linked to invasive fungal infections, it is clear that our present 3 classes of antifungal agents may not be sufficient to provide optimal management to these fragile patients. Furthermore, with widespread use of antifungal agents, drug-resistant fungal infections are on the rise. Therefore, there is some urgency to develop the antifungal pipeline with the goal of new antifungal agent discovery. In this review, a simple metabolic pathway, which forms the disaccharide, trehalose, will be characterized and its potential as a focus for antifungal target(s) explained. It possesses several important features for development of antifungal agents. First, it appears to have fungicidal characteristics and second, it is broad spectrum with importance across both ascomycete and basidiomycete species. Finally, this pathway is not found in mammals so theoretically specific inhibitors of the trehalose pathway and its enzymes in fungi should be relatively non-toxic for mammals. The trehalose pathway and its critical enzymes are now in a position to have directed antifungal discovery initiated in order to find a new class of antifungal drugs.
authors.affiliation: a Departments of Medicine and Biochemistry , Duke University Medical Center , Durham , NC , USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Perfect
authors.affiliation: a Departments of Medicine and Biochemistry , Duke University Medical Center , Durham , NC , USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Tenor
authors.affiliation: a Departments of Medicine and Biochemistry , Duke University Medical Center , Durham , NC , USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Miao
authors.affiliation: a Departments of Medicine and Biochemistry , Duke University Medical Center , Durham , NC , USA.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Brennan
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015725:Fluconazole / Q000494:pharmacology / Q000627:therapeutic use; D005658:Fungi / Q000187:drug effects* / Q000201:enzymology; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000187:drug effects*; D009181:Mycoses / Q000188:drug therapy; D014199:Trehalose / Q000378:metabolism*
chemical_list: D000935:Antifungal Agents; D004791:Enzyme Inhibitors; D015725:Fluconazole; D014199:Trehalose; D005964:Glucosyltransferases; C023180:trehalose-6-phosphate synthase
keywords: antifungal; drug development; trehalose