Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb). It is latent in one-third of the world’s population and is one of the top ten causes of death worldwide. Currently, most feasible diagnostics in low resource settings take days to weeks to perform and suffer from poor sensitivity. Therefore, there is a critical need for diagnostic probes that can rapidly and selectively label mycobacteria and can be analyzed with available infrastructure. The Mtb cell wall is highly complex, consisting of several layers, including a hydrophobic mycomembrane that can incorporate extracellular trehalose, a type of sugar. Previously, the Bertozzi Group synthesized a solvatochromic fluorophore, 4-N,N-dimethylamino-1,8-naphthalimide (4-DMN), and attached it to trehalose (Tre) for incorporation into the mycomembrane. Solvatochromic dyes shift in color or intensity based on the electronic properties of the surrounding solvent. 4-DMN does not label bacterial species that lack trehalose glycolipids, and it fluoresces strongly in the mycomembrane but not in the surrounding solution. These properties of 4-DMN result in good signal over background without the requirement for a washing step, lending itself to streamlined diagnostic technologies. However, 4-DMN has a similar background signal to the autofluoresence signal of most cells, complicating the ability to differentially measure mycobacterial incorporation of DMN-Tre. Thus, improvements in color, intensity of fluorescence, and pharmacokinetics are necessary. The goal of this research is to develop a new probe based on solvatochromic 3-methoxychromone derivatives that maximizes bacterial mycomembrane labeling, minimizes background labeling, and has favorable host membrane penetrance. Candidate probes will be designed and screened in silico using the computational program Gaussian. The probes will then be used to study the effects of different conditions in mycobacterial cell wall dynamics in macrophages and eventually in zebrafish, a model organism for Mtb infection.

Synthesis of solvatochromic probes to label the mycobacterial cell wall

253rd National Meeting (2017)

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