Mechanism-based inhibition of HsaD: a C-C bond hydrolase essential for survival of Mycobacterium tuberculosis in macrophage

Ali Ryan, Sebastian Keany, Olga Eleftheriadou, Romain Ballet, Hung-Yuan Cheng, Edith Sim

Research output: Contribution to journalArticle (Academic Journal)peer-review

5 Citations (Scopus)
315 Downloads (Pure)

Abstract

Mycobacterium tuberculosis remains the leading cause of death by a bacterial pathogen worldwide. Increasing prevalence of multidrug-resistant organisms means prioritizing identification of targets for antituberculars. 2-hydroxy-6-oxo-6-phenylhexa-2,4-dienoate hydrolase (HsaD), part of the cholesterol metabolism operon, is vital for survival within macrophage. The C-C bond hydrolase, HsaD, has a serine protease-like catalytic triad. We tested a range of serine protease and esterase inhibitors for their effects on HsaD activity. As well as providing a potential starting point for drug development, the data provides evidence for the mechanism of C-C bond hydrolysis. This screen also provides a route to initiate development of fragment-based inhibitors.

Original languageEnglish
Pages (from-to)42-47
Number of pages6
JournalFEMS Microbiology Letters
Volume350
Issue number1
Early online date1 Jan 2014
DOIs
Publication statusPublished - Jan 2014

Keywords

  • Antitubercular Agents
  • Cholinesterase Inhibitors
  • Drug Design
  • Fatty Acids, Unsaturated
  • Hydrolases
  • Hydrolysis
  • Inhibitory Concentration 50
  • Macrophages
  • Microbial Viability
  • Models, Molecular
  • Mycobacterium tuberculosis
  • Protein Conformation
  • Pseudomonas
  • Serine Proteinase Inhibitors
  • Spectrometry, Mass, Electrospray Ionization
  • Journal Article

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