Mycobacterium tuberculosis disrupted in a 13-gene operon (mce1) accumulates free
mycolic acids (FM) in its cell wall and causes accelerated death in mice. Here, to more comprehensively analyze differences in their cell wall
lipid composition, we used an untargeted metabolomics approach to compare the
lipid profiles of wild-type and mce1 operon mutant strains. By liquid chromatography-mass spectrometry, we identified >400 distinct
lipids significantly altered in the mce1 mutant compared to wild type. These
lipids included decreased levels of saccharolipids and
glycerophospholipids, and increased levels of alpha-, methoxy- and keto
mycolic acids (MA), and hydroxyphthioceranic
acid. The mutant showed reduced expression of mmpL8, mmpL10, stf0, pks2 and
papA2 genes involved in transport and metabolism of
lipids recognized to induce proinflammatory response; these
lipids were found to be decreased in the mutant. In contrast, the transcripts of mmpL3, fasI, kasA, kasB, acpM and RV3451 involved in MA transport and metabolism increased; MA inhibits inflammatory response in macrophages. Since the mce1 operon is known to be regulated in intracellular M.
tuberculosis, we speculate that the differences we observed in cell wall lipid metabolism and composition may affect host response to M.
tuberculosis infection and determine the clinical outcome of such an
infection.