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Structure Guided Design Of Biotin Protein Ligase Inhibitors For Antibiotic Discovery.
MedLine Citation:
PMID:  24236729     Owner:  NLM     Status:  Publisher    
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 of antibacterial discovery. Most BPL's 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.
Ashleigh S Paparella; Tatiana P Soares da Costa; Min Y Yap; William Tieu; Matthew C J Wilce; Grant W Booker; Andrew D Abell; Steven W Polyak
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-11-10
Journal Detail:
Title:  Current topics in medicinal chemistry     Volume:  -     ISSN:  1873-4294     ISO Abbreviation:  Curr Top Med Chem     Publication Date:  2013 Nov 
Date Detail:
Created Date:  2013-11-18     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101119673     Medline TA:  Curr Top Med Chem     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Department of Biochemistry, School of Molecular and Biomedical Sciences, University of Adelaide, Adelaide, SA 5005, Australia.
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