jm061068d_si_001.pdf (2.14 MB)
Antitubercular Nucleosides That Inhibit Siderophore Biosynthesis: SAR of the Glycosyl Domain
journal contribution
posted on 2006-12-28, 00:00 authored by Ravindranadh V. Somu, Daniel J. Wilson, Eric M. Bennett, Helena I. Boshoff, Laura Celia, Brian J. Beck, Clifton E. Barry, Courtney C. AldrichTuberculosis is the leading cause of infectious disease mortality in the world by a bacterial pathogen. We
previously demonstrated that a bisubstrate inhibitor of the adenylation enzyme MbtA, which is responsible
for the second step of mycobactin biosynthesis, exhibited potent antitubercular activity. Here we systematically
investigate the structure−activity relationships of the bisubstrate inhibitor glycosyl domain resulting in the
identification of a carbocyclic analogue that possesses a KIapp value of 2.3 nM and MIC99 values of 1.56 μM
against M. tuberculosis H37Rv. The SAR data suggest the intriguing possibility that the bisubstrate inhibitors
utilize a transporter for entry across the mycobacterial cell envelope. Additionally, we report improved
conditions for the expression of MbtA and biochemical analysis, demonstrating that MbtA follows a random
sequential enzyme mechanism for the adenylation half-reaction.
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sequential enzyme mechanismAntitubercular NucleosidesSAR dataGlycosyl DomainTuberculosisantitubercular activitymycobactin biosynthesis1.56 μ Mbisubstrate inhibitorbisubstrate inhibitor glycosyl domaincarbocyclic analoguebisubstrate inhibitorstuberculosis H 37Rvadenylation enzyme MbtAmycobacterial cell envelopeMIC 99 values2.3 nMKIapp valuedisease mortality
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