Recent advances toward the inhibition of mAG and LAM synthesis in Mycobacterium tuberculosis

Drug-resistant forms of Mycobacterium tuberculosis (M. tuberculosis) are increasing worldwide, underscoring the need to develop new drugs to treat the disease. One of the factors that make tuberculosis difficult to treat is the unique architecture of the mycobacterial cell wall. In this review, we catalogue the enzymes involved in the synthesis of the mycolylarabinogalactan (mAG), a key structural component of the mycobacterial cell wall. In addition, we review the enzymes required for the synthesis of the related lipoarabinomannan (LAM), a structure that possesses immunomodulatory properties. The integrity of the mAG and LAM is critical to the viability of mycobacteria, and many of the established antimycobacterial agents target enzymes critical to the synthesis of the mAG and LAM. Recently, new enzymes catalyzing synthetic steps in the synthesis of the mAG and LAM have been characterized and their substrate specificity determined. In this report, we review recent efforts to characterize the enzymes involved in mAG and LAM synthesis and describe the compounds used to inhibit the enzymes or characterize their catalytic activity.