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The role of chemoenzymatic synthesis in advancing trehalose analogues as tools for combatting bacterial pathogens
- Source :
- Chem Commun (Camb)
- Publication Year :
- 2020
- Publisher :
- Royal Society of Chemistry (RSC), 2020.
-
Abstract
- Trehalose, a disaccharide of glucose, is increasingly recognized as an important contributor to virulence in major bacterial pathogens, such as Mycobacterium tuberculosis, Clostridioides difficile, and Burkholderia pseudomallei. Accordingly, bacterial trehalose metabolic pathways that are not present in humans have gained traction as targets for antibiotic and diagnostic development. Toward this goal, trehalose can be modified through a combination of rational design and synthesis to produce functionalized trehalose analogues, which can be deployed to probe or inhibit bacterial trehalose metabolism. However, the unique α,α-1,1-glycosidic bond and C(2) symmetry of trehalose make analogue synthesis via traditional chemical methods very challenging. We and others have turned to the creation of chemoenzymatic synthesis methods, which in principle allow the use of nature’s trehalose-synthesizing enzymes to stereo- and regioselectively couple simple, unprotected substrates to efficiently and conveniently generate trehalose analogues. Here, we provide a contextual account of our team’s development of a trehalose analogue synthesis method that employs a highly substrate-tolerant, thermostable trehalose synthase enzyme, TreT from Thermoproteus tenax. Then, in three vignettes, we highlight how chemoenzymatic synthesis has accelerated the development of trehalose-based imaging probes and inhibitors that target trehalose-utilizing bacterial pathogens. We describe the role of TreT catalysis and related methods in the development of (i) tools for in vitro and in vivo imaging of mycobacteria, (ii) anti-biofilm compounds that sensitize drug-tolerant mycobacteria to clinical anti-tubercular compounds, and (iii) degradation-resistant trehalose analogues that block trehalose metabolism in C. difficile and potentially other trehalose-utilizing bacteria. We conclude by recapping progress and discussing priorities for future research in this area, including improving the scope and scale of chemoenzymatic synthesis methods to support translational research and expanding the functionality and applicability of trehalose analogues to study and target diverse bacterial pathogens.
- Subjects :
- Burkholderia pseudomallei
Disaccharide
Virulence
01 natural sciences
Article
Catalysis
03 medical and health sciences
chemistry.chemical_compound
Drug Resistance, Bacterial
Materials Chemistry
030304 developmental biology
chemistry.chemical_classification
Thermoproteus
0303 health sciences
biology
Clostridioides difficile
010405 organic chemistry
Metals and Alloys
Rational design
Trehalose
Mycobacterium tuberculosis
General Chemistry
biology.organism_classification
0104 chemical sciences
Surfaces, Coatings and Films
Electronic, Optical and Magnetic Materials
Metabolic pathway
Enzyme
Biochemistry
chemistry
Glucosyltransferases
Biofilms
Trehalose metabolism
Biocatalysis
Ceramics and Composites
Fluorescein
Bacteria
Subjects
Details
- ISSN :
- 1364548X and 13597345
- Volume :
- 56
- Database :
- OpenAIRE
- Journal :
- Chemical Communications
- Accession number :
- edsair.doi.dedup.....95cd5297802e6d432d26161ecb1f7784
- Full Text :
- https://doi.org/10.1039/d0cc04955g