Inhibition studies of ketol-acid reductoisomerases from pathogenic microorganisms

Shun Jie Wun, Lambro A. Johnson, Lv You, Ross P. McGeary, Thomas Brueck, Gerhard Schenk, Luke W. Guddat

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Ketol-acid reductoisomerase (KARI), the second enzyme in the branched-chain amino acid (BCAA) biosynthesis pathway, is an emerging target for the discovery of biocides. Here, we demonstrate that cyclopropane-1,1-dicarboxylate (CPD) inhibits KARIs from the pathogens Mycobacterium tuberculosis (Mt) and Campylobacter jejuni (Cj) reversibly with Ki values of 3.03 μM and 0.59 μM, respectively. Another reversible inhibitor of both KARIs, Hoe 704, is more potent than CPD with Ki values of 300 nM and 110 nM for MtKARI and CjKARI, respectively. The most potent inhibitor tested here is N-hydroxy-N-isopropyloxamate (IpOHA). It has a Ki of ~26 nM for MtKARI, but binds rather slowly (kon ~900 M−1s−1). In contrast, IpOHA binds more rapidly (kon ~7000 M−1s−1) to CjKARI and irreversibly.

Original languageEnglish
Article number108516
JournalArchives of Biochemistry and Biophysics
Volume692
DOIs
StatePublished - 15 Oct 2020

Keywords

  • Antimicrobial chemotherapeutics
  • Branched-chain amino acid biosynthesis
  • Campylobacter jejuni
  • Ketol-acid reductoisomerase
  • Mycobacterium tuberculosis

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