Siderophore-Mediated Iron Acquisition: Target for the Development of Selective Antibiotics Towards Mycobacterium tuberculosis - Iron Acquisition by the Genus Mycobacterium - page 78

Fig. 5.15 DltA-specific inhibitor ( 63 ) and ascamycin ( 64 ) [ 75 ]
Fig. 5.16 Salicyl-adenylate inhibitor of mycobactin and yersiniabactin [ 76 ]
(IC 50 = 39.9 ± 7.6 μ M) perhaps by other mode of action. Compound 65 repre-
sents the first biochemically confirmed inhibitor of siderophore biosynthesis.
Somu et al. [ 73 ] have further explored the syntheses of nucleoside antibiotics that
target MbtA, an adenylate-forming enzyme that activates salicylic acid and loads it
onto a thiol group of mycobactin TB in a two-step process (Fig. 5.17 ). Like other
A-domain modules, the lack of mammalian homologues, makes MbtA an attractive
target for the development of antibacterial agents. The bisubstrate inhibitors were
designed based on adenylate intermediate 60 considering that its A-domain binding
was 3-5 orders of magnitude greater than that of the salicylic acid. The tight binding
prevents the loss of the intermediate to the surroundings or hydrolysis.
Initial work focused on modification of the phosphate linker and substitution
on the salicyl aryl moiety 65 , 67 - 68 (Fig. 5.18 ). Inhibitor 65 was designed based
on the natural product ascamycin ( 64 ). The hydroxyl group in the salicyl moiety
was demonstrated to modulate the acidity of the NH proton of the linker through
delocalization. The acylsulfamate linker proved to be unstable and in order to
overcome this limitation, all analogs were prepared as the corresponding triethyl-
ammonium salts [ 73 ].
The nucleoside inhibitors were screened against M. tuberculosis H 37 Rv
under iron-limiting conditions to test affinity, stability and permeability
across the mycobacterial cell envelope. Acylsulfamide analog 69 (Fig. 5.18 ),
designed to improve overall stability, displayed the highest inhibitory activity
(MIC 99 = 0.19 μ M), comparing favorably with isoniazid (MIC 99 = 0.18 μ M).