Antitubercular Nucleosides That Inhibit Siderophore Biosynthesis: SAR of the Glycosyl Domain
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- 作者：Ravindranadh V. Somu ; Daniel J. Wilson ; Eric M. Bennett ; Helena I. Boshoff ; Laura Celia ; Brian J. Beck ; Clifton E. Barry ; III ; Courtney C. Aldrich
- 刊名：Journal of Medicinal Chemistry
- 出版年：2006
- 出版时间：December 28, 2006
- 年：2006
- 卷：49
- 期：26
- 页码：7623 - 7635
- 全文大小：251K
- 年卷期：v.49,no.26(December 28, 2006)
- ISSN：1520-4804
文摘
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 
Magainst 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.
Magainst 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.