Structure-activity relationships at the 5-position of thiolactomycin: An intact (5R)-isoprene unit is required for activity against the condensing enzymes from Mycobacterium tuberculosis and Escherichia coli

Pilho Kim, Yong Mei Zhang, Gautham Shenoy, Quynh Anh Nguyen, Helena I. Boshoff, Ujjini H. Manjunatha, Michael B. Goodwill, John Lonsdale, Allen C. Price, Darcie J. Miller, Ken Duncan, Stephen W. White, Charles O. Rock, Clifton E. Barry, Cynthia S. Dowd

Research output: Contribution to journalArticle

77 Citations (Scopus)

Abstract

Thiolactomycin inhibits bacterial cell growth through inhibition of the β-ketoacyl-ACP synthase activity of type 11 fatty acid synthases. The effect of modifications of the 5-position isoprenoid side chain on both IC 50 and MIC were determined. Synthesis and screening of a structurally diverse set of 5-position analogues revealed very little tolerance for substitution in purified enzyme assays, but a few analogues retained MIC, presumably through another target. Even subtle modifications such as reducing one or both double bonds of the diene were not tolerated. The only permissible structural modifications were removal of the isoprene methyl group or addition of a methyl group to the terminus. Cocrystallization of these two inhibitors with the condensing enzyme from Escherichia coli revealed that they retained the TLM binding mode at the active site with reduced affinity. These results suggest a strict requirement for a conjugated, planar side chain inserting within the condensing enzyme active site.

Original languageEnglish
Pages (from-to)159-171
Number of pages13
JournalJournal of Medicinal Chemistry
Volume49
Issue number1
DOIs
Publication statusPublished - 12-01-2006

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Fingerprint Dive into the research topics of 'Structure-activity relationships at the 5-position of thiolactomycin: An intact (5R)-isoprene unit is required for activity against the condensing enzymes from Mycobacterium tuberculosis and Escherichia coli'. Together they form a unique fingerprint.

  • Cite this

    Kim, P., Zhang, Y. M., Shenoy, G., Nguyen, Q. A., Boshoff, H. I., Manjunatha, U. H., Goodwill, M. B., Lonsdale, J., Price, A. C., Miller, D. J., Duncan, K., White, S. W., Rock, C. O., Barry, C. E., & Dowd, C. S. (2006). Structure-activity relationships at the 5-position of thiolactomycin: An intact (5R)-isoprene unit is required for activity against the condensing enzymes from Mycobacterium tuberculosis and Escherichia coli. Journal of Medicinal Chemistry, 49(1), 159-171. https://doi.org/10.1021/jm050825p