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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Antitubercular nucleosides that inhibit siderophore biosynthesis: SAR of the glycosyl domain
Journal of Medicinal Chemistry, Volume 49, No. 26, Year 2006
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Description
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 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. © 2006 American Chemical Society.
Authors & Co-Authors
Wilson, Daniel J.
United States, Minneapolis
University of Minnesota Twin Cities
Boshoff, Helena Ingrid M.
United States, Bethesda
National Institute of Allergy and Infectious Diseases Niaid
Beck, Brian J.
Unknown Affiliation
Barry, Clifton Earl
United States, Bethesda
National Institute of Allergy and Infectious Diseases Niaid
Aldrich, Courtney C.
United States, Minneapolis
University of Minnesota Twin Cities
Statistics
Citations: 77
Authors: 5
Affiliations: 2
Identifiers
Doi:
10.1021/jm061068d
ISSN:
00222623