Siderophore-Mediated Iron Acquisition: Target for the Development of Selective Antibiotics Towards Mycobacterium tuberculosis - Iron Acquisition by the Genus Mycobacterium - page 70

sideromycins [ 50 , 51 ]. The biological activity of synthetic sideophore-conjugates
provided evidence that selective and, in certain cases, potent inhibitors can be
developed by target the iron-uptake as a target [ 52 ].
5.5 Mycobactin Analogs are Growth Inhibitors of M.
tuberculosis
G. A. Snow performed extensive siderophore work with the isolation and charac-
terization of the mycobactins. The early realization that exogenous mycobactins
could disrupt mycobacterial growth led to the study and chemical syntheses of
analogs in search of potential inhibitors of M. tuberculosis (Fig. 5.6 ) [ 30 ]. Maurer
and Miller reported the synthesis of mycobactin S2 ( 17 , MbS2), the first example
of an iron-binding capable synthetic mycobacterial siderophore [ 53 ]. However, 17
did not display growth inhibitory activity against M. tuberculosis . The lack of a
long alkyl chain proved to be important for biological activity, as demonstrated
with the synthesis of MbS ( 18 ), which effectively inhibited M. tuberculosis H 37 Rv
(MIC 99 = 12.5 μ g/mL, 15.6 μ M). Stereochemistry at the ester region of the
mycobactin core was proven to be critical. While 18 was a potent inhibitor of M.
tuberculosis , the synthetic ( R )-epimer mycobactin T ( 19 ) was a growth promoter
[ 54 ]. Structurally related to the mycobactins, amamistatin B is a natural prod-
uct secreted by the actinomycete Nocardia asteroides . Fennell and collaborators
reported the syntheses and biological activity of amamistatin B analogs ( 20 - 22 ),
where only analog 20 was found to display modest growth inhibition against M.
tuberculosis (MIC = 47 μ M) [ 55 ].
Pursuing the synthesis of a mycobactin-antibiotic conjugate, Miller et al. [ 56 ,
57 ] reported analog 23 (Fig. 5.7 ). In order to incorporate a chemical handle for
further manipulation, the ester region of the siderophore was modified to contain a
2,3-diaminopropionate spacer. Remarkably, 23 itself, with a N -Boc protecting group
was found to be a potent inhibitor of M. tuberculosis H 37 Rv (MIC < 0.2 μ g/mL)
Fig. 5.6 Synthetic mycobactin and amamistatin analogs [ 61 , 55 ]