# Chemoenzymatic synthesis of trehalose analogues as tools for investigating mycobacteria

> **NIH NIH R15** · CENTRAL MICHIGAN UNIVERSITY · 2024 · $445,611

## Abstract

Project Summary/Abstract: Tuberculosis and related mycobacterial diseases are challenging to treat in part
due to the extraordinary tolerance of mycobacteria to drugs. Despite the identification of trehalose metabolism
as a key contributor to mycobacterial drug tolerance and a promising target for therapeutic development, there
has been limited progress toward elucidating the roles of trehalose metabolic pathways in mycobacterial
physiology and pathogenesis, and in exploiting these pathways for applications in basic and translational
research. As established in the prior periods of this award, trehalose analogues 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 of the research is to better
understand and target mycobacterial trehalose metabolism. The objectives of this project are to harness
chemoenzymatic synthesis to develop trehalose analogues as tools for mycobacteria research, with a focus in
the next period on novel tools to investigate and address mycobacterial drug tolerance. These objectives will be
achieved through three specific aims, each of which employs chemoenzymatic synthesis methods: (Aim 1)
Develop trehalose analogues as trehalose metabolism modulators; (Aim 2) Develop trehalose monomycolate
(TMM) analogues as cell envelope permeability modulators; and (Aim 3) Develop trehalose analogues as
immune modulators. In Aim 1, the TreT catalysis method for trehalose analogue synthesis developed in the prior
periods will be improved in reaction scope and scale and applied toward the synthesis and characterization of
trehalose-based inhibitors of TreS-mediated metabolic remodeling in mycobacteria. In Aim 2, chemoenzymatic
methods will be used to synthesize trehalose monomycolate analogues as tools for studying and impairing cell
envelope permeability toward drugs in mycobacteria. In Aim 3, chemoenzymatic synthesis will aid the
development of trehalose-based antibody-recruiting molecules and strategies, which will be investigated for their
ability to augment the host immune response to mycobacteria. 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 analogues for mycobacteria research; (ii) while trehalose analogues
have been applied extensively in imaging applications, this project will shift focus to developing novel tools for
studying and addressing the problem of mycobacterial drug tolerance. 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, virulence, and drug tolerance in numerous mycobacterial pathogens. This project will
continue to support the interdisciplinary training of undergr...

## Key facts

- **NIH application ID:** 10875313
- **Project number:** 2R15AI117670-03
- **Recipient organization:** CENTRAL MICHIGAN UNIVERSITY
- **Principal Investigator:** Benjamin Michael Swarts
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $445,611
- **Award type:** 2
- **Project period:** 2015-01-16 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10875313

## Citation

> US National Institutes of Health, RePORTER application 10875313, Chemoenzymatic synthesis of trehalose analogues as tools for investigating mycobacteria (2R15AI117670-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10875313. Licensed CC0.

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