Antitubercular Nucleosides That Inhibit Siderophore Biosynthesis:  SAR of the Glycosyl Domain

Ravindranadh V. Somu,† Daniel J. Wilson,† Eric M. Bennett,† Helena I. Boshoff,‡ Laura Celia,§ Brian J. Beck,§ Clifton E. Barry, III,‡ and Courtney C. Aldrich*†
Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, Minnesota 55455, Tuberculosis Research Section, National Institute of Allergy and Infectious Diseases, Rockville, Maryland 20852-1742, and Bacteriology Program, American Type Culture Collection, Manassas, Virginia 20110
J. Med. Chem., 2006, 49 (26), pp 7623–7635
DOI: 10.1021/jm061068d
Publication Date (Web): December 21, 2006
Copyright © 2006 American Chemical Society
†

 University of Minnesota.

,
‡

 National Institute of Allergy and Infectious Diseases.

,
§

 American Type Culture Collection.

,
*

 To whom correspondence should be addressed. Phone:  612-625-7956. Fax:  612-626-5173. E-mail:  aldri015@umn.edu.

Abstract

Abstract Image

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.

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  • Published In Issue December 28, 2006
  • Received September 11, 2006

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