Siderophore-Mediated Iron Acquisition: Target for the Development of Selective Antibiotics Towards Mycobacterium tuberculosis - Iron Acquisition by the Genus Mycobacterium - page 83

position improved the activity against MbtI with compounds 120 - 122 display-
ing potent activity, 120 (K i = 11 ± 1 μ M). These compounds represent the most
potent inhibitors of MbtI or any other salicylate synthase reported to date.
5.10 Conclusions
Iron acquisition has been validated as a biological target to develop novel antibacte-
rial agents. Siderophores are metal chelators utilized by bacteria to obtain iron under
iron-limited environments such as a human host. Because of the global health impact
of TB, there is the need of developing novel antibiotics that can be used alongside
the current first-line drugs. Interestingly, simple analogs of the hydrophobic sidero-
phores used by M. tuberculosis have proven to be potent and selective growth
inhibitors, although the specifics regarding their precise mode of action remain to
be elucidated. Exploiting nature's own design, mycobactin-artemisinin conjugate
56 was synthesized and demonstrated to be a potent and highly selective anti-TB
agent (MIC = 0.39 μ g/mL, M. tuberculosis H 37 Rv). A different approach to tar-
get iron acquisition is the synthesis of inhibitors targeting the enzymes involved
in siderophore assembly. The advantage of this work relies on the lack of human
homologues, rendering the analogues as ideal candidates for human use. Specific
examples of these molecules already display activity that rivals that of isoniazid ( 69 ,
MIC 99 = 0.19 μ M, M. tuberculosis H 37 Rv), the most commonly used antibiotic
against M. tuberculosis today. Regardless of the approach taken, these molecules
provide the knowledge and tools largely needed to deal with the burden of TB.
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