Drug target/mechanism: PA-824 possibly acts via generation of radicals having non-specific toxic effects; however the drug has been shown to inhibit mycolic acid and protein biosynthesis. Specific inhibition of mycolic acid and protein synthesis: using Mycobacterium bovis BCG strain, in the presence of PA-824, protein synthesis (incorporation of ~(35)S) and lipid synthesis (uptake of ~(14)C-acetate into mycolic acid precursors) were both inhibited in a drug-dependent manner. Concentrations of hydroxymycolate, a precursor for ketomycolate, rose significantly under low drug (<1 mug/ml) but fell as drug concentrations increased; ketomycolate concentrations decreased with increasing drug, suggesting that PA-824 might act at or around this metabolic step. Protein synthesis was also inhibited in a drug-dependent manner but an intriguing accumulation in labeled proteins at <1 mug/ml drug remains to be explained.
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