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Biosynthesis and Pathogenic Role of the M. tuberculosis Cell Envelope

The Mtb cell envelope differs substantially from the cell walls of gram-positive and gram-negative bacteria and contains many unique lipid and glycolipid molecules, including mycolic acids, lipoarabinomannan, trehalose dimycolate, and phthiocerol dimycocerosate. While the structures of many of these molecules have been defined in exquisite chemical detail, their role in pathogenesis has only recently become clear with genetic studies in M. tuberculosis. To understand the role of these unique chemical entities in pathogenesis, we and others have generated defined mutants of M. tuberculosis that lack specific components of the cell envelope. We have focused on the cyclopropane modification of mycolic acids, a lipid modification that is present in diverse bacteria, but is especially elaborate in M. tuberculosis (and absent from saprophytic mycobacteria). We have focused on a family of S-adenosyl methionine-dependent methyltransferases of M. tuberculosis that modify mycolic acids with cyclopropyl groups and methyl branches. By studying null mutants in each methyltransferase and combinations of methyltransferase, we have:

  • Defined the biosynthetic role of each methyltransferase in mycolic acid modification
  • Demonstrated that site- and stereochemically specific mycolic acid cyclopropanation has an important role in Mtb pathogenesis
  • Demonstrated that cyclopropanation of mycolic acids on trehalose dimycolate acts directly to activate (cis cyclopropanation) or repress (trans-cyclopropanation) host innate immune activation
  • Validated the mycolic acid methyltransferases as a drug target through a chemical inhibitor (1) and creation of an M. tuberculosis strain lacking all cyclopropanation (2)
Mycolic acid modification in <em>M. tuberculosis</em> -- The structure of the three major mycolic acid classes (alpha, methoxy, and keto) are shown. Each cyclopropane ring or methyl branch is annotated with the name of the gene encoding the methyltransferase required for the synthesis of that modification. For details, see references below.