Tuberculosis (TB), an infectious disease caused by the bacterial pathogen <i>Mycobacterium tuberculosis </i>(Mtb), is one of the top ten causes of death worldwide and is thought to be latent in one-third of the world’s population. There is an urgent need for novel antibiotics to treat drug resistant TB, but the disparity between in vitro and in vivo efficacy has proved an obstacle to drug development. This difference in efficacy is thought to be due in part to the effect of the host microenvironment on the epigenetic and metabolic state of the bacterium, but a dearth of appropriate chemical probes for noninvasive monitoring of infection in a living model organism has made this hypothesis difficult to investigate until recently. This study involves synthesis and characterization of derivatives of a mycobacteria-selective probe recently developed by other researchers in the Bertozzi Group. In the original probe, a solvatochromic fluorophore called 4-<i>N,N</i>-dimethylamino-1,8-naphthalimide (4-DMN) was attached to trehalose (Tre), a sugar that is incorporated into a layer of the mycobacterial cell wall called the mycomembrane. Solvatochromic dyes shift in color or intensity based on the electronic properties of the surrounding environment. Dyes such as 4-DMN fluoresce most strongly in extremely hydrophobic environments such as the mycomembrane, resulting in good signal over background even without washing away excess unincorporated probe, a necessity for in vivo applications. While DMN-Tre is a promising new labeling reagent, there is still room for optimization of the probe's color, intensity of fluorescence, and pharmacokinetics. This research focuses on development of a range of solvatochrome-trehalose probes that will be used to study changes in mycobacterial cell wall dynamics in cell culture and eventually in zebrafish, a model organism for Mtb infection.

Synthesis of solvatochromic probes to study the effect of host microenvironment on mycobacterial cell wall dynamics during infection

253rd National Meeting (2017)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.