RECOGNITION OF MULTIPLE EFFECTS OF ETHAMBUTOL ON METABOLISM OF MYCOBACTERIAL CELL-ENVELOPE

Ethambutol is known to rapidly inhibit biosynthesis of the arabinan co mponent of the mycobacterial cell wall core polymer, arabinogalactan ( K. Takayama and J. O. Kilburn, Antimicrob. Agents Chemother. 33:1493-1 499, 1989), This effect was confirmed, and it was also shown that etha mbutol inhibits biosynthesis of the arabinan of lipoarabinomannan, a l ipopolysaccharide noncovalently associated with the cell wall core, In contrast to cell wall core arabinan, which is completely inhibited by ethambutol, synthesis of the arabinan of lipoarabinomannan was only p artially affected, demonstrating a differential effect on arabinan syn thesis in the two locales, Further studies of the effect of ethambutol on cell wall biosynthesis revealed that the synthesis of galactan in the cell wall core is strongly inhibited by the drug, In addition, eth ambutol treatment resulted in the cleavage of arabinosyl residues pres ent in the mycobacterial cell wall; more than 50% of the arabinan in t he cell wall core was removed from the wall 1 h after addition of the drug to growing mycobacterial cultures, In contrast, galactan,vas not released from the cell wall during ethambutol treatment, The natural f unction of the arabinosyl-releasing enzyme remains unknown, but its ac tion in combination with inhibition of synthesis during ethambutol tre atment results in severe disruption of the mycobacterial cell wall, Ac cordingly, ethambutol-induced damage to the cell wall provides a ready molecular explanation for the known synergetic effects of ethambutol with other chemotherapeutic agents, Nevertheless, the initial direct e ffect of ethambutol remains to be elucidated.