BIOGENESIS OF THE MYCOBACTERIAL CELL-WALL AND THE SITE OF ACTION OF ETHAMBUTOL

The effect of ethambutol (EMB) is primarily on polymerization steps in the biosynthesis of the arabinan component of cell wall arabinogalact an (AG) of Mycobacterium smegmatis. Inhibition of the synthesis of the arabinan of lipoarabinomannan (LAM) occurred later, and thus in the c ases of AG and LAM, the polymerization of D-arabinofuranose apparently involves separate pathways, While the synthesis of these arabinans wa s normal in an EMB-resistant isogeneic strain, the addition of EMB to the resistant strain resulted in partial inhibition of the synthesis o f the arabinan of LAM and the emergence of a novel, truncated form of LAM, indicating partial susceptibility of the resistant gene(s) and pr oviding a new intermediate in the LAM biosynthetic sequence. A consequ ence of inhibition of AG arabinan biosynthesis is the lack of new site s for mycolate attachment and thus the channeling of mycolate residues into a variety of free lipids which then accumulate, The primary bioc hemical effects of EMB can be explained by postulating separate AG and LAM pathways catalyzed by a variety of extramembranous arabinosyl tra nsferases with various degrees of sensitivity to EMB.