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ACS Med Chem Lett. 2012 May 23;3(6):509-14. doi: 10.1021/ml300106p. eCollection 2012 Jun 14.

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

Author information

1
School of Molecular and Biomedical Science and School of Chemistry and Physics, University of Adelaide , South Australia 5005, Australia.
2
School of Biomedical Science, Monash University , Victoria, 3800, Australia.
3
Microbiology and Infectious Diseases Directorate, SA Pathology, Women's and Children's Hospital , South Australia 5006, Australia.
4
School of Molecular and Biomedical Science and School of Chemistry and Physics, University of Adelaide , South Australia 5005, Australia ; Microbiology and Infectious Diseases Directorate, SA Pathology, Women's and Children's Hospital , South Australia 5006, Australia.

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.

KEYWORDS:

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

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