Mycobactin synthesis

The latest knowledge with respect to the chemistry and functions of mycobactins may be exploited skilfully in a wide spectrum of approaches to the intensive and extensive search for antimycobacterial drugs. In actual practice, one such approach may essentially involve critical and exhaustive screening of compounds that interfere at certain specific point in the pathway of biosynthesis of mycobactins and selecting only such compounds which inhibited exclusively the bacterial growth rmder iron-limiting conditions. Thus, one may justifiably link up the primary role of action of /r r -aminosalicylic acid (PAS) with the ensuing inhibition of the mycobactin synthesis. 

Pharmacology Aminosalicylic acid is bacteriostatic against Mycobacterium tuberculosis. It inhibits the onset of bacterial resistance to streptomycin and isoniazid. The mechanism of action has been postulated to be inhibition of folic acid synthesis (but without potentiation with antifolic compounds) or inhibition of synthesis of the cell wall component, mycobactin, thus reducing iron uptake by M. tuberculosis. 

On saponification mycobactin splits Into mycobactic acid and cobactin. Synthetic studies Black et at., /lust J, Chem. 25t 2155 (1972). Synthesis of mycobactin S2 p. J. Maurer, M. J, Miller, /. Am. Chem. Soc. 105, 240 (1983). Review of early studies Rose, Snow, Mycobactin A Growth Factor for Acid-Fast Bacilli in G. E. W, Wol-stenholme, M, P. Cameron, C. M. O Connor, Ciba Foundation Symposium on Expti. Tuberculosis Bacillus and Host 1955, 41-54. Comprehensive review Snow Bacterial. Rev, 34, 99 (1970). 

Siderophores are produced by microorganisms to overcome the risk of Fe deficiency. The biosynthesis of siderophores and the intermediates SA or 2,3-DHBA is therefore dependent on Fe availability [57,68,74]. The production of 2,3-DHBA-glycine in B. subtilis is inversely proportional to the amount of iron in the culture [117]. When iron is available the Fe(2,3-DHBA)3 complex is involved in the control of the biosynthesis [117]. The production of mycobactin is repressed by high levels of Fe or Fe and Zir, SA concentration increased both when Fe and Fe were omitted from the medium [118]. The biosynthesis of pyochelin can also be reduced by other transition metals like Co, Mo , Ni ", and Cu [82] It seemed that iron inhibits the activities of the enzymes required for the biosynthesis of SA or 2,3-DHBA [78,119]. Iron is not an inhibitor of the activity of the enzymes themselves, but it influences the synthesis of the enzymes [120,121]. 

A feedback inhibition has been detected in B. subtilis, using the ferrisiderophore reductase. This enzyme reduces iron from the ferrisiderophore. The rate at which the ferrisiderophore reductase reduces iron from ferrisiderophores may signal the aromatic pathway about the demand for chorismic acid for 2,3-DHBA synthesis [128,129]. The reductase may have a regulatory effect on chorismate synthase activity. Chorismate synthase may have oxidizable sulfhydryl groups that, when oxidized, may slow the synthesis of chorismic acid [128-130]. There seemed to be no repression or inhibitory effect of 2,3-DHBA or SA on its own biosynthesis [78,121]. Also the endproduct mycobactin (sole endproduct) does not inhibit SA biosynthesis [78]. 

Alkylation of hydroxamic acids as a method of co-N-hydroxyamino acids (2) synthesis was introduced by Maurer and Miller 196), When N- r -butoxycarbonyl-6-hydroxynorleucine benzylhydroxamate (248) or a homologue was treated with triphenylphosphine and diethylazodi-carboxylate (DEAD) under Mitsunobu conditions 197), intramolecular alkylation took place leading to N-hydroxylactams (249) or (250) as well as lesser amounts of hydroximates Z-(251) and -(252) (Scheme 50). The products were separated and distinguished by NMR spectrometry 196,198,199). Derivatives of the seven-membered N-hydroxylactam (253) were applied for the total synthesis of mycobactin S2 (254) 199) (Scheme 51). 

Black, D.S.C., R.F.C. Brown, and A.M. Wade Synthetic Studies Related to Myco-bactins. II. Formation of Mycobactin Hydroxamic Acid Units by Malonic Esters Synthesis. Austral. J. Chem. 25, 2155 (1972). 

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