Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis (TB),
is the leading bacterial cause of infectious disease mortality. The current WHOapproved
treatment for TB involves a three- or four-drug regimen comprising isoniazid,
rifampin, pyrazinamide, and/or ethambutol for a minimum of 6 months.
While these first-line agents remain useful in treating susceptible Mycobacterium
tuberculosis strains, the emergence of multidrug resistant tuberculosis demands the
development of new drugs [1].
Iron acquisition is an essential process for M. tuberculosis as well as almost all
other microorganisms. However, this essential micronutrient is highly sequestered
in a mammalian host. In response to iron starvation, Mtb produces small-molecule
iron chelators, a pair of related peptidic siderophores known as mycobactin and carboxymycobactins
that vary by the appended lipid residue termed siderophores [4, 5,
7, 8]. Because mycobactins are critical for growth and virulence of M. tuberculosis,
they have emerged as attractive targets for the development of anti-TB agents [4].
Biosynthesis of mycobactin is initiated by the aryl acid adenylation enzyme
MbtA which activates salicylic acid forming an acyladenylate intermediate (Sal-
AMP). MbtA is also responsible for loading the acyladenylate intermediate onto
the thiolation domain of MbtB-SH – the enzyme taking part in the next step of
biosynthesis process [10].
Given the documented importance of many siderophores for virulence and lack
of human aryl acid adenylation enzymes homologues, several analogues possessing
stable linkers as bioisosteres of the labile acyl phosphate function have been synthesized
as the potent enzyme inhibitors [13]. The initial lead compound 5’-O-[N-
(salicyl)sulfamoyl]adenosine (Sal-AMS) has emerged as a promising inhibitor of
MbtA and was shown to possess promising whole-cell activity toward M. tuberculosis.
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