Biotin analogues with antibacterial activity are potent inhibitors of biotin protein ligase

Tatiana P Soares da Costa, William Tieu, Min Y. Yap, Ondrej Zvarec, Jan M Bell, John D Turnidge, John C. Wallace, Grant William Booker, Matthew C. J. Wilce, Andrew D. Abell, Steven W Polyak

Research output: Contribution to journalArticleResearchpeer-review

28 Citations (Scopus)

Abstract

There is a desperate need to develop new antibiotic agents to combat the rise of drug-resistant bacteria, such as clinically important Staphylococcus aureus. The essential multifunctional enzyme, biotin protein ligase (BPL), is one potential drug target for new antibiotics. We report the synthesis and characterization of a series of biotin analogues with activity against BPLs from S. aureus, Escherichia coli, and Homo sapiens. Two potent inhibitors with K i < 100 nM were identified with antibacterial activity against a panel of clinical isolates of S. aureus (MIC 2-16 μg/mL). Compounds with high ligand efficiency and >20-fold selectivity between the isozymes were identified and characterized. The antibacterial mode of action was shown to be via inhibition of BPL. The bimolecular interactions between the BPL and the inhibitors were defined by surface plasmon resonance studies and X-ray crystallography. These findings pave the way for second-generation inhibitors and antibiotics with greater potency and selectivity. 

Original languageEnglish
Pages (from-to)509-514
Number of pages6
JournalACS Medicinal Chemistry Letters
Volume3
Issue number6
DOIs
Publication statusPublished - 14 May 2012

Keywords

  • antibiotic
  • biotin protein ligase
  • enzyme
  • enzyme inhibitor
  • medicinal chemistry

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