Siderophore-Mediated Iron Acquisition: Target for the Development of Selective Antibiotics Towards Mycobacterium tuberculosis - Iron Acquisition by the Genus Mycobacterium - page 75

Fig. 5.12 Structure-activity relationship of mycobactin component “A” [ 63 , 64 , 65 ]
molecular weight, Log P, good in vitro stability, are orally bioavailable and have
an acceptable therapeutic index with lack of toxicity against human cell lines [ 63 ].
5.7 A Mycobactin Siderophore-Antibiotic Conjugate
Selectively Targets M . tuberculosis
Siderophore-antibiotic drug conjugates have demonstrated the potential to be
strong and selective inhibitors of bacteria. Siderophores that are recognized by a
unique strain are of particular interest. To explore if mycobactin T analogs could
be used to deliver antibiotics into M. tuberculosis , Miller et al. reported the assem-
bly of mycobactin-artemisinin conjugate 56 (Fig. 5.13 ) [ 56 ]. Artemisinin is an
endo-peroxide containing antibiotic used to treat P. falciparum , the causative agent
of malaria. The conjugate was proven to be a potent inhibitor of M. tuberculosis
H 37 Rv (MIC = 0.39 μ g/mL), with remarkable inhibition of MDR M. tuberculosis
(MIC = 0.16-1.25 μ g/mL), and XDR M. tuberculosis (MIC = 0.078-0.625 μ g/
mL). Mycobactin conjugate 56 was found inactive against a panel of Gram-
positive and Gram-negative bacteria but inhibited four strains of P. falcipa-
rum (IC 50 = 0.004-0.0051 μ g/mL). The results were consistent with the fact
that the synthetic mycobactin T analogs and the artemisinin core do not display
broad antibiotic activity. However, the artemisinin peroxide moiety is sufficient
to inhibit P. falciparum . To confirm the observed activity, desferrioxamine-arte-
misinin conjugate 58 was synthesized. As expected, 58 inhibited P. falciparum
(IC 50 > 2.2-0.16 μ M) but was found to be inactive against M. tuberculosis H 37 Rv.
This work confirmed that selectivity of sideromycins can be modulated through