Structure guided design of biotin protein ligase inhibitors for antibiotic discovery.
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.
Ashleigh S
AS
Paparella
Tatiana P
TP
Soares da Costa
Min Y
MY
Yap
William
W
Tieu
Matthew C J
MC
Wilce
Grant W
GW
Booker
Andrew D
AD
Abell
Department of Biochemistry, School of Molecular and Biomedical Sciences, University of Adelaide, Adelaide, SA 5005, Australia. steven.polyak@adelaide.edu.au.
Steven W
SW
Polyak
D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D001710:Biotin / Q000031:analogs & derivatives / Q000378:metabolism*; D019731:Carbon-Nitrogen Ligases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D015195:Drug Design; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D058990:Molecular Targeted Therapy; D011487:Protein Conformation; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D013211:Staphylococcus aureus / Q000187:drug effects
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D029968:Escherichia coli Proteins; D012097:Repressor Proteins; D001710:Biotin; D000255:Adenosine Triphosphate; D019731:Carbon-Nitrogen Ligases; C058125:birA protein, E coli; D000103:Acetyl-CoA Carboxylase