Siderophore-Mediated Iron Acquisition: Target for the Development of Selective Antibiotics Towards Mycobacterium tuberculosis - Iron Acquisition by the Genus Mycobacterium - page 76

Fig. 5.13 Mycobactin-artemisinin conjugate. The antibiotic moiety (artemisinin) is highlighted
in blue [ 61 , 56 ]
the siderophore portion as demonstrated by the bacterial specificity, or through the
antibiotic moiety as observed by artemisinin's spectrum of activity.
5.8 Inhibition of MbtA Nonribosomal Peptide Synthetase
Because the biosynthesis of mycobactin T is essential for the growth of M. tuber-
culosis under iron-limited conditions [ 67 , 68 ], the enzymes involved in the assem-
bly of the siderophore have become targets for the development of novel antibiotic
agents. The biosynthesis of mycobactin T is performed by a mixed nonribosomal
peptide synthetase polyketide synthase (NRPS-PKS) assembly line. The genes
encoding for the siderophore machinery are clustered in two regions, the myco-
bactin T - 1 cluster contains the enzymes involved in the synthesis of the mycobac-
tin core, while mycobactin T - 2 performs the activation and incorporation of the
hydrophobic tail [ 69 - 70 ]. NRPS are enzymes that catalyze multistep reactions.
Organized in modules, NRPS assist the incorporation of amino acid residues unto
bacterial metabolites. The A-domain of these enzymes activates a specific sub-
strate to form an acyl adenylate intermediate ( 60 , Fig. 5.14 ) in an ATP-dependent
process [ 71 , 72 , 73 ]. Such activity is related to the aminoacyl tRNA synthetases
although there is no sequence, nor structural relationship between them. Finking
et al. [ 74 ], reported the first study to develop A-domain inhibitors through the
synthesis of analogs 61 and 62 . These compounds were screened against two