Chemical Probes of Mycobacteria

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Project Summary/Abstract Section The rise of resistant strains of Mycobacterium tuberculosis (Mtb) demands new approaches to combating this infectious agent. The survival of Mtb depends on the cell envelope, which is both durable and dynamic. Mycobacteria modulate their cell envelope composition to subsist in the harsh environments they encounter in the host. The proposed aims focus on developing new tools to probe, perturb, and observe changes in the mycobacterial cell envelope. The focus of Aim 1 is on visualizing arabinofuranose and mannose residues within the cell wall and the immunomodulatory lipoarabinomannan (LAM). In Aim 2, we shall develop a complementary probe that identifies methylthioxylofuranose (MTX)-capped LAM, a glycan that has been detected in pathogenic mycobacteria. The probes generated in Aims 1 and 2 can reveal how cell envelope composition varies under different conditions and between strains. In Aim 3, we shall deploy a fluorogenic probe to visualize the changing mycobacterial cell envelope in real time. This probe provides a means to explore phenotypic changes in the mycobacterial cell envelope upon antibiotic treatment or uptake into macrophages. By pursuing the three aims, we expect to uncover vulnerabilities in mycobacterial defenses that will lead to new antibiotic strategies. Significance: The overall objective of this application is to develop new chemical probes to understand how the mycobacteria modify and maintain their cell envelope to survive under the extreme and varied conditions they encounter in human hosts. We anticipate that this knowledge will ultimately lead to the identification of new strategies to treat tuberculosis (TB).