| Abstract
| - Tuberculosis is the leading cause of infectious disease mortality in the world by a bacterial pathogen. Wepreviously demonstrated that a bisubstrate inhibitor of the adenylation enzyme MbtA, which is responsiblefor the second step of mycobactin biosynthesis, exhibited potent antitubercular activity. Here we systematicallyinvestigate the structure−activity relationships of the bisubstrate inhibitor glycosyl domain resulting in theidentification of a carbocyclic analogue that possesses a KIapp value of 2.3 nM and MIC99 values of 1.56 μMagainst M. tuberculosis H37Rv. The SAR data suggest the intriguing possibility that the bisubstrate inhibitorsutilize a transporter for entry across the mycobacterial cell envelope. Additionally, we report improvedconditions for the expression of MbtA and biochemical analysis, demonstrating that MbtA follows a randomsequential enzyme mechanism for the adenylation half-reaction.
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