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Current Topics in Medicinal Chemistry


ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

Structure Guided Design of Biotin Protein Ligase Inhibitors for Antibiotic Discovery

Author(s): Ashleigh S. Paparella, Tatiana P. Soares da Costa, Min Y. Yap, William Tieu, Matthew C. J. Wilce, Grant W. Booker, Andrew D. Abell and Steven W. Polyak

Volume 14 , Issue 1 , 2014

Page: [4 - 20] Pages: 17

DOI: 10.2174/1568026613666131111103149

Price: $65


Biotin protein ligase (BPL) represents a promising target for the discovery of new antibacterial chemotherapeutics. Here we review the central role of BPL for the survival and virulence of clinically important Staphylococcus aureus in support of this claim. X-ray crystallography structures of BPLs in complex with ligands and small molecule inhibitors provide new insights into the mechanism of protein biotinylation, and a template for structure guided approaches to the design of inhibitors for antibacterial discovery. Most BPLs employ an ordered ligand binding mechanism for the synthesis of the reaction intermediate biotinyl-5´-AMP from substrates biotin and ATP. Recent studies reporting chemical analogs of biotin and biotinyl-5´-AMP as BPL inhibitors that represent new classes of anti-S. aureus agents are reviewed. We highlight strategies to selectively inhibit bacterial BPL over the mammalian equivalent using a 1,2,3-triazole isostere to replace the labile phosphoanhydride naturally present in biotinyl-5´-AMP. A novel in situ approach to improve the detection of triazole-based inhibitors is also presented that could potentially be widely applied to other protein targets.

Keywords: Antibiotic, biotin, biotin protein ligase, Staphylococcus aureus, structure guided drug design, inhibitor design, Xray crystallography.

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