Format

Send to

Choose Destination
J Med Chem. 2006 Dec 28;49(26):7623-35.

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

Author information

1
Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, MN 55455, USA.

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.

PMID:
17181146
PMCID:
PMC2526467
DOI:
10.1021/jm061068d
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for American Chemical Society Icon for PubMed Central
Loading ...
Support Center