The effect of p-aminosalicyclic acid on iron transport and assimilation in mycobacteria.
p-Aminosalicylic acid inhibits growth of Mycobacterium bovis BCG and Mycobacterium smegmatis more effectively if cells are growing with a sufficiency of iron (more than 1 mu g Fe/ml) in the medium than if cells are deficient in iron (smaller than 0.1 mu g Fe/ml). In iron-deficient cultures formation of mycobactin, an ionophore for iron transport, is strongly inhibited by p-aminosalicylic acid. Uptake of iron into cell suspensions is also inhibited and the activity of several iron-containing enzymes declines in cells exposed to p-aminosalicylic acid during their growth. p-Aminosalicylic acid is about 50 times more effective towards a mutant of M. smegmatis which required mycobactin under iron-deficient growth conditions than towards the wild-type parent. p-Aminosalicylate is taken up into cells by an active process independent of the salicylate uptake system, possibly by the route used for assimilation of p-aminobenzoate. (This could account for why p-aminobenzoic acid, but not salicylic acid, antagonizes the action of p-aminosalicylic acid.) With iron-deficient cells, salicylate assimilation is about 50 times greater than either p-aminosalicylate or p-aminobenzoate but with iron-sufficient cells and with the mycobactin mutant salicylate uptake is negligible whereas p-aminobenzoate and p-aminosalicylate uptakes are unaffected. p-Aminosalicylic acid at 3.3 mM (500 mu g/ml) partially inhibits the uptake of both p-aminobenzoate and, if it is occurring, that of salicylate as well. As p-aminosalicylic acid is always more effective when the intracellular concentration of salicylic acid is low, it probably acts as an anti-metabolite of salicylic acid, not, however, by inhibiting the conversion of salicylic acid to mycobactin, but probably somewhere along the metabolic pathway of iron uptake.
D062365:Aminobenzoates / Q000378:metabolism; D000636:Aminosalicylic Acids / Q000378:metabolism / Q000494:pharmacology*; D000963:Antimetabolites / Q000494:pharmacology; D001692:Biological Transport; D002474:Cell-Free System; D006133:Growth Substances / Q000096:biosynthesis; D007501:Iron / Q000378:metabolism*; D000090463:Iron Deficiencies; D009154:Mutation; D009161:Mycobacterium / Q000187:drug effects / Q000378:metabolism*; D009163:Mycobacterium bovis / Q000187:drug effects / Q000378:metabolism*; D010080:Oxazoles / Q000096:biosynthesis; D012459:Salicylates / Q000378:metabolism
D062365:Aminobenzoates; D000636:Aminosalicylic Acids; D000963:Antimetabolites; D006133:Growth Substances; D010080:Oxazoles; D012459:Salicylates; D007501:Iron