<i>Mycobacterium tuberculosis</i> and other species in the <i>Corynebacterineae</i> suborder have a unique outer membrane called the mycomembrane (MM). The MM is robust permeability barrier that is essential to pathogenesis, thus it is an important target for tuberculosis drug development. Standard methods used to study mycolic acid-containing components of the mycomembrane are often inconvenient and do not allow for analysis of intact, single cells. Bioorthogonal chemical reporters that tag specific mycomembrane components may facilitate the identification and isolation of these structures, as well as provide information about the mechanisms involved in mycomembrane biosynthesis. Recently, a chemical reporter that mimics trehalose monomycolate (TMM)—but instead of a native mycolate chain it has a truncated, “clickable” alkyne-modified acyl chain—was used in cells to report on Ag85-catalyzed mycoloylation processes that are the cornerstone of mycomembrane biogenesis. Here, we report the synthesis of new TMM-mimicking probes with varying chain length and different chemical reporter groups. These probes enabled optimization of this metabolic labeling method and provided the ability to probe mycoloylation in living bacterial cells for the first time.

Synthesis and evaluation of an expanded set of chemical reporters for probing mycoloylation in mycobacteria

253rd National Meeting (2017)

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