Exposure of Mycobacteria to Cell Wall-inhibitory Drugs Decreases Production of Arabinoglycerolipid Related to Mycolyl-arabinogalactan-peptidoglycan Metabolism

Abstract

Background: Mycolyl-arabinogalactan-peptidoglycan (mAGP) represents the hallmark of the mycobacterial cell envelope and the target of several antitubercular drugs. Results: Loss of a glycolipid structurally analogous to the terminal portion of mAGP correlates with drug treatment in mycobacteria. Conclusion:This work establishes the versatility of arabinoglycerolipids in M. tuberculosis. Significance: Further work will define the importance of the metabolic relationship between the two components in cell wall remodeling and/or pathogenesis.

Structural Determination and Toll-like Receptor 2-dependent Proinflammatory Activity of Dimycolyl-diarabino-glycerol from Mycobacterium marinum

“…Structure of Mycobacterium marinum DMAG-We have recently shown that several slow-growing mycobacterial species, including M. bovis BCG, M. tuberculosis, and Mma produce an apolar cell wall-associated glycolipid whose synthesis was altered by several anti-tubercular drugs inhibiting arabinogalactan or mycolic acid biosynthesis (33). Structural elucidation of this product in M. bovis…”

“…Mma_DMAG was then purified by two successive rounds of absorption chromatography, as reported earlier (33). Briefly, the crude apolar extract was dissolved in chloroform and fractionated by silica gel column flash chromatography.…”

“…Recently, this amphipathic hydrophobic glycolipid was identified in the cell wall of other slow-growing mycobacterial species including M. tuberculosis, Mycobacterium bovis BCG, Mycobacterium scrofulaceum, and Mma (33). Structural analyses demonstrated that DMAG from M. bovis BCG is analogous to the terminal portion of mycolylarabinogalactan-peptidoglycan, consisting in 5-O-mycolyl-␤-Araf-(132)-5-O-mycolyl-␣-Araf-(131)-Gro (DMAG) (33).…”

“…Recently, this amphipathic hydrophobic glycolipid was identified in the cell wall of other slow-growing mycobacterial species including M. tuberculosis, Mycobacterium bovis BCG, Mycobacterium scrofulaceum, and Mma (33). Structural analyses demonstrated that DMAG from M. bovis BCG is analogous to the terminal portion of mycolylarabinogalactan-peptidoglycan, consisting in 5-O-mycolyl-␤-Araf-(132)-5-O-mycolyl-␣-Araf-(131)-Gro (DMAG) (33). Moreover, exposure to anti-tubercular drugs (thiacetazone, ethambutol) known to interfere with the mAGP and mycolate biosynthesis altered DMAG production in both Mma and M. bovis BCG, leading to the hypothesis of a metabolic relationship between DMAG and mAGP (33).…”

“…Structural analyses demonstrated that DMAG from M. bovis BCG is analogous to the terminal portion of mycolylarabinogalactan-peptidoglycan, consisting in 5-O-mycolyl-␤-Araf-(132)-5-O-mycolyl-␣-Araf-(131)-Gro (DMAG) (33). Moreover, exposure to anti-tubercular drugs (thiacetazone, ethambutol) known to interfere with the mAGP and mycolate biosynthesis altered DMAG production in both Mma and M. bovis BCG, leading to the hypothesis of a metabolic relationship between DMAG and mAGP (33). In addition, the presence of anti-DMAG antibodies in patients infected with M. avium strongly suggested that DMAG is an immunogenic compound produced (or released from the cell wall) during infection (34).…”