, 2007). As the mechanism of iron acquisition by mycobacteria is unique to these bacteria, this provides a number of possible targets for drug action that will not be found in other microorganisms or, and most importantly, in the host. Such suggestions have already been made on the basis of mutants of

pathogenic mycobacteria losing their virulence in animal models when components of iron acquisition mechanism have been deleted (De Voss et al., 2000; Luo et al., 2005; Somu et al., 2006). The central molecule that is involved in iron acquisition CX 5461 in almost all mycobacteria is mycobactin. This is a lipophilic, small-molecular-weight siderophore that is located in the envelope of mycobacteria in close proximity to the cytoplasmic membrane (Ratledge, 1999). Although it has a very high affinity for iron (Ks∼1036), it does not directly sequester iron from the host as it is insufficiently water soluble for

this task and cannot come into direct contact with any iron-containing molecules of the host; instead, a related siderophore, carboxymycobactin, is secreted by pathogenic mycobacteria, which is then the functional extracellular siderophore. Both mycobactin and carboxymycobactin are considered to be synthesized by a common pathway, with divergence to the two siderophores occurring at one of the last stages (Ratledge, 2004). The pathway for mycobactin/carboxymycobactin involves the initial synthesis of salicylic acid via the shikimic acid

pathway; this is then linked to various amino acids or their derivatives to yield the final siderophore (Quadri Y 27632 et al., 1998). Deletion of any one of the three genes (trpE2, entC or entD) that are involved in the biosynthesis of salicylate from chorismic acid in Mycobacterium smegmatis results in the impairment of growth particularly under conditions when iron is at a limiting concentration (Nagachar & Ratledge, 2010). Similar results were reported when salicylate-requiring auxotrophs of M. smegmatis were generated by random mutagenesis (Ratledge & Hall, 1972; Adilakshmi et al., 2000). It is therefore our contention that the antitubercular drug p-aminosalicylate (PAS) acts as an analogue Digestive enzyme of salicylic acid and either inhibits its synthesis or, more likely, its onward conversion to mycobactin. PAS was one of the first antituberculosis drugs (Lehmann, 1946). As its discovery pre-dated the elucidation of the structure of mycobactin (Snow, 1965), it was suggested both then and later by numerous writers (e.g. Winder, 1964) that its mode of action was that of an antifolate drug as it seemingly could be regarded as an analogue of p-aminobenzoate, the aromatic precursor of folic acid. More recent evidence suggests that the linkage of PAS to folate metabolism could be at the level of thymidylate synthase (ThyA), whose gene, when mutated, leads to PAS resistance in M. tuberculosis (Rengarajan et al., 2004; Mathys et al., 2009).