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Type: Journal article
Title: Biotin analogues with antibacterial activity are potent inhibitors of biotin protein ligase
Author: Soares da Costa, T.
Tieu, W.
Yap, M.
Zvarec, O.
Bell, J.
Turnidge, J.
Wallace, J.
Booker, G.
Wilce, M.
Abell, A.
Polyak, S.
Citation: ACS Medicinal Chemistry Letters, 2012; 3(6):509-514
Publisher: American Chemical Society
Issue Date: 2012
ISSN: 1948-5875
Statement of
Tatiana P. Soares da Costa, William Tieu, Min Y. Yap, Ondrej Zvarec, Jan M. Bell, John D. Turnidge, John C. Wallace, Grant W. Booker, Matthew C. J. Wilce, Andrew D. Abell, and Steven W. Polyak
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: biotin protein ligase; enzyme; enzyme inhibitor; antibiotic; medicinal chemistry
Rights: © 2012 American Chemical Society
RMID: 0020120426
DOI: 10.1021/ml300106p
Appears in Collections:Molecular and Biomedical Science publications

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