Trehalose biosynthesis pathway as a promising new target for antifungal drug development

Abstract

High mortality rates associated with systemic mycoses have dramatically increased in immunocompromised patients. With limitedly available antifungal drugs and their adverse drug reactions, much effort is being focused on new antifungal drug development. Fungi have evolved multifactorial mechanisms to survive various stress conditions encountered in the environment and in vivo during infection. Targeting the biochemical pathways utilized by the fungus to adapt to stress conditions is one proposed approach for the development of new antifungal drugs. Biosynthesis of the disaccharide trehalose is one such target that is not found in humans. The TPS/TPP pathway is the main mechanism fungi utilized for trehalose biosynthesis and has been found to have a critical role in regulating fungal metabolic homeostasis and integrity of fungal cell wall. Mutants  tps2 and trehalose-6-phosphate phosphatase activity displayed an increased accumulation of trehalose-6-phosphate intermediate, cell wall alteration, and attenuation of the virulence in the murine models of systemic mycoses. The consistent results were found in human fungal pathogens; Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus suggesting that the trehalose biosynthesis pathway is a promising target for antifungal drug development. However, finding a broad spectrum fungicidal drug against human fungal pathogens must also consider the outcome on the pathogenic dimorphic fungi. Importantly, the consequences of host immune responses against fungi must also be taken into account when the fungal cell wall exhibits changes through the inhibition of the trehalose biosynthesis pathway.