Adenozyno-5’-o-(n-acylosulfamoilowe) pochodne jako potencjalne leki przeciwgruźlicze
Journal Title: Wiadomości Chemiczne - Year 2016, Vol 70, Issue 7
Abstract
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.
Authors and Affiliations
Katarzyna Kulik, Janina Baraniak
Keywords
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