Trehalose-6-phosphate phosphatase as a broad-spectrum therapeutic target against eukaryotic and prokaryotic pathogens

Abstract

As opposed to organism-based drug screening approaches, protein-based strategies have the distinct advantage of providing insights into the molecular mechanisms of chemical effectors and thus afford a precise targeting. Capitalising on the increasing number of genome and transcriptome datasets, novel targets in pathogens for therapeutic intervention can be identified in a more rational manner when compared with conventional organism-based methodologies. Trehalose-6-phosphate phosphatases (TPPs) are structurally and functionally conserved enzymes of the trehalose biosynthesis pathway which play a critical role for pathogen survival, in particular, in parasites. The absence of these enzymes and trehalose biosynthesis from mammalian hosts has recently given rise to increasing interest in TPPs as novel therapeutic targets for drugs and vaccines. Here, we summarise some key aspects of the current state of research towards novel therapeutics targeting, in particular, nematode TPPs.

Characterisation of trehalose-6-phosphate phosphatases from bacterial pathogens

“…One target for novel antimicrobials is the enzyme trehalose-6-phosphate phosphatase (TPP; E.C. number 3.1.3.12) [17], a conserved enzyme of the commonest of five known trehalose biosynthesis pathways. This enzyme is found in many pathogens, including bacteria, nematodes and yeast, but absent from mammalian hosts and catalyses the last step in the so-called OtsAB pathway of trehalose synthesis from uridine diphosphate-glucose and glucose 6-phosphate [18].…”

A suicide inhibitor of nematode trehalose-6-phosphate phosphatases

“…Of the five known trehalose biosynthesis pathways, the so-called OtsAB pathway is the most common and employs trehalose-6-phosphate phosphatase (TPP; Enzyme Commission number 3.1.3.12) for the dephosphorylation of trehalose-6-phosphate (T6P), which is synthesised from uridine diphosphate-glucose and glucose-6-phosphate by trehalose-6-phosphate synthase 21 . The observation that TPP knockdown results in lethal phenotypes in the free-living nematode Caenorhabditis elegans 22 and Mycobacterium tuberculosis 23 , combined with the high conservation of this biosynthetic enzyme in pathogenic species 19 has recently focused efforts of target-based drug discovery on pathogen TPPs (reviewed in 24 ).…”

Trehalose 6‐phosphate phosphatases ofPseudomonas aeruginosa

“…In addition to the treYZ pathway, another 4 additional pathways of trehalose biosynthesis have been observed in prokaryotes, plants, fungi, and nonvertebrate animals. Among those other pathways, the so-called osmotically regulated trehalose synthesis (ots)AB pathway has attracted particular attention as a target of interest for therapeutic intervention in infectious diseases [reviewed in Cross et al (12)] because accumulation of the metabolite trehalose 6-phosphate (T6P) results in a lethal phenotype in Caenorhabditis elegans and Mycobacterium tuberculosis (13,14).…”