Targeting multiple chorismate-utilizing enzymes with a single inhibitor: Validation of a three-stage design

Kristin T. Ziebart, Seth M. Dixon, Belem Avila, Mohamed H. El-Badri, Kathryn G. Guggenheim, Mark J. Kurth, Michael D. Toney

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Chorismate-utilizing enzymes are attractive antimicrobial drug targets due to their absence in humans and their central role in bacterial survival and virulence. The structural and mechanistic homology of a group of these inspired the goal of discovering inhibitors that target multiple enzymes. Previously, we discovered seven inhibitors of 4-amino-4-deoxychorismate synthase (ADCS) in an on-bead, fluorescent-based screen of a 2304-member one-bead-one-compound combinatorial library. The inhibitors comprise PAYLOAD and COMBI stages, which interact with active site and surface residues, respectively, and are linked by a SPACER stage. These seven compounds, and six derivatives thereof, also inhibit two other enzymes in this family, isochorismate synthase (IS) and anthranilate synthase (AS). The best binding compound inhibits ADCS, IS, and AS with K i values of 720, 56, and 80 μM, respectively. Inhibitors with varying SPACER lengths show the original choice of lysine to be optimal. Lastly, inhibition data confirm the PAYLOAD stage directs the inhibitors to the ADCS active site.

Original languageEnglish (US)
Pages (from-to)3718-3729
Number of pages12
JournalJournal of Medicinal Chemistry
Volume53
Issue number9
DOIs
StatePublished - May 13 2010

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Anthranilate Synthase
Catalytic Domain
Enzymes
Lysine
Virulence
Survival
Pharmaceutical Preparations
aminodeoxychorismate synthase
isochorismate synthase

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Ziebart, K. T., Dixon, S. M., Avila, B., El-Badri, M. H., Guggenheim, K. G., Kurth, M. J., & Toney, M. D. (2010). Targeting multiple chorismate-utilizing enzymes with a single inhibitor: Validation of a three-stage design. Journal of Medicinal Chemistry, 53(9), 3718-3729. https://doi.org/10.1021/jm100158v

Targeting multiple chorismate-utilizing enzymes with a single inhibitor : Validation of a three-stage design. / Ziebart, Kristin T.; Dixon, Seth M.; Avila, Belem; El-Badri, Mohamed H.; Guggenheim, Kathryn G.; Kurth, Mark J.; Toney, Michael D.

In: Journal of Medicinal Chemistry, Vol. 53, No. 9, 13.05.2010, p. 3718-3729.

Research output: Contribution to journalArticle

Ziebart, KT, Dixon, SM, Avila, B, El-Badri, MH, Guggenheim, KG, Kurth, MJ & Toney, MD 2010, 'Targeting multiple chorismate-utilizing enzymes with a single inhibitor: Validation of a three-stage design', Journal of Medicinal Chemistry, vol. 53, no. 9, pp. 3718-3729. https://doi.org/10.1021/jm100158v
Ziebart, Kristin T. ; Dixon, Seth M. ; Avila, Belem ; El-Badri, Mohamed H. ; Guggenheim, Kathryn G. ; Kurth, Mark J. ; Toney, Michael D. / Targeting multiple chorismate-utilizing enzymes with a single inhibitor : Validation of a three-stage design. In: Journal of Medicinal Chemistry. 2010 ; Vol. 53, No. 9. pp. 3718-3729.
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