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Antitubercular nucleosides that inhibit siderophore biosynthesis: SAR of the glycosyl domain.


ABSTRACT: Tuberculosis 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 microM 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.

SUBMITTER: Somu RV 

PROVIDER: S-EPMC2526467 | biostudies-literature | 2006 Dec

REPOSITORIES: biostudies-literature

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Antitubercular nucleosides that inhibit siderophore biosynthesis: SAR of the glycosyl domain.

Somu Ravindranadh V RV   Wilson Daniel J DJ   Bennett Eric M EM   Boshoff Helena I HI   Celia Laura L   Beck Brian J BJ   Barry Clifton E CE   Aldrich Courtney C CC  

Journal of medicinal chemistry 20061201 26


Tuberculosis 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  ...[more]

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