Many bacterial cell wall glycans are potent virulence factors and drivers of infectious disease. For example, in Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis, cell wall glycans play a key role in mediating infection of host tissues and modulation of the host immune response. However, there are few means by which to site-selectively modify and label these glycans in order to study their functions in disease pathogenesis. This is due to the fact that glycans often lack reactive functional group diversity that would be amenable to standard bioconjugation strategies. Therefore, there is a need for new tools with which to investigate the role of bacterial cell glycans. Methylthioxylofuranose (MTX) is a monosaccharide appended to an antigenic glycolipid in the Mtb cell wall that contains a unique thioether moiety. The privileged reactivity of the thioether over other functional groups can thus be exploited for selective bioconjugation. Previously, oxaziridine reagents have been used to label the thioether of methionine residues in proteins, but this chemistry has yet to be applied to glycans. We expanded the use of oxaziridine bioconjugation to glycans by labeling the MTX monosaccharide in Mtb. We have validated this approach by labeling MTX containing glycans in vitro, which is the first application of oxaziridine-thioether chemistry to label a glycan. Furthermore, we have demonstrated that this approach can be used to label and visualize the Mtb cell wall in vivo. These studies will enable future work investigating dynamic changes to a key Mtb cell wall component during tuberculosis infection or antibiotic treatment, helping to identify new opportunities and strategies for therapeutic intervention, as well as expand the repertoire of glycan bioconjugation strategies.

Exploiting thioether reactivity for labeling mycobacterial glycans

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