Sunday, November 24, 2024
11/24/2024
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 undergraduate students in a biomedical research area of high importance, and it will enhance the institutions’ research environments, in part through continued development and utilization of a biocontainment facility for research on pathogenic mycobacteria.
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