Mycobacterium tuberculosis, the causative agent of tuberculosis, causes over 1.4 million deaths worldwide per year. Mycobacteria possess a highly protective outer membrane, which plays a key role in the bacterium’s innate drug tolerance. It consists of large (up to C90) hydrophobic lipids, notably the major mycolic acid conjugates arabinogalactan-linked mycolate (AGM) and trehalose dimycolate (TDM). Both AGM and TDM are synthesized from the precursor trehalose monomycolate (TMM), whose mycoloyl group is transferred by Ag85 mycoloyltransferase enzymes onto acceptor glycans to build AGM and TDM. Our lab has previously shown that TMM analogues with unnatural acyl chains can incorporate into AGM and TDM via Ag85. We hypothesize that growing mycobacteria in the presence of synthetic TMM variants containing severely truncated acyl groups may replace the native mycolates in AGM and TDM, consequently increasing the permeability of the outer membrane to small molecules such as antibiotics. To enable testing of this hypothesis, we developed TMM analogues with C6, C14, and C22 fatty acyl groups and conducted permeability assays along with growth inhibition assays in the presence of antibiotics to assess the impact of TMM analogue treatment of mycobacteria. We previously reported the synthesis of these compounds. Here we report their evaluation through the described biological assays conducted in the model organism Mycobacterium smegmatis.

Synthesis and evaluation of chain-truncated trehalose mycolate derivatives for chemical remodeling of the mycobacterial outer membrane

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