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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 C2 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.

The role of chemoenzymatic synthesis in advancing trehalose analogues as tools for combatting bacterial pathogens