# Chemoenzymatic Synthesis of Trehalose Analogues as Tools for Investigating Bacterial Pathogens

> **NIH NIH R15** · CENTRAL MICHIGAN UNIVERSITY · 2020 · $450,778

## Abstract

Project Summary/Abstract: Despite the emergence of bacterial trehalose metabolism as a promising target for
antibiotic and diagnostic development, there has been limited progress toward elucidating trehalose metabolic
pathways, probing their roles in bacterial growth and virulence, and leveraging them for applications ranging
from basic research to the detection and treatment of challenging infections. As established in the first period of
this award, trehalose-based imaging probes and inhibitors can serve as powerful tools to drive progress in these
areas. However, the challenges associated with the synthesis of trehalose analogues has severely impeded their
development and applications. The long-term goal is to better understand bacterial trehalose metabolism and to
exploit this knowledge for antibiotic and diagnostic development. The objectives of this project are to: (i) harness
chemoenzymatic synthesis to create a functionally diverse toolbox of trehalose-based probes and inhibitors; and
(ii) apply this toolbox to elucidate trehalose utilization characteristics of diverse bacteria and to develop inhibitors
of trehalose metabolism in important pathogens. These objectives will be achieved through three specific aims:
(Aim 1) Develop chemoenzymatic methods for the synthesis of trehalose and trehalose-6-phosphate (T6P)
analogues; (Aim 2) Develop and apply detectable trehalose analogues to probe bacterial trehalose metabolism;
and (Aim 3) Develop trehalose analogues as inhibitors of bacterial trehalose metabolism. In Aim 1, the TreT
catalysis method for trehalose analogue synthesis developed in the prior award period will be improved in
reaction scope and scale, and new chemoenzymatic methods will be developed to synthesize analogues of T6P,
which is an essential metabolite in many bacteria. In Aim 2, labeled trehalose analogues will be
chemoenzymatically synthesized and used to profile trehalose uptake characteristics in diverse bacteria and
define the species-selectivity of trehalose-based imaging probes developed in the prior period. In Aim 3, based
on results obtained in the first award period, rationally-designed trehalose-based inhibitors targeting trehalose
utilization pathways in M. tuberculosis and C. difficile will be developed and evaluated using enzymatic and
bacterial culture assays. This application is innovative because: (i) instead of traditional chemical synthesis,
chemoenzymatic methods will be used to substantially increase the diversity, functionality, and accessibility of
trehalose and T6P analogues for microbiology research; (ii) while trehalose analogues have been applied nearly
exclusively to mycobacteria, this project will expand the usage of these tools to other types of bacteria. This
research is significant because it will produce new synthetic methods, tool compounds, and strategies to
investigate and target trehalose metabolism, which is critical to growth and virulence in numerous bacterial
pathogens. This project w...

## Key facts

- **NIH application ID:** 9880785
- **Project number:** 2R15AI117670-02
- **Recipient organization:** CENTRAL MICHIGAN UNIVERSITY
- **Principal Investigator:** Benjamin Michael Swarts
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $450,778
- **Award type:** 2
- **Project period:** 2015-01-16 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9880785

## Citation

> US National Institutes of Health, RePORTER application 9880785, Chemoenzymatic Synthesis of Trehalose Analogues as Tools for Investigating Bacterial Pathogens (2R15AI117670-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9880785. Licensed CC0.

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