1 research outputs found
Biotin Analogues with Antibacterial Activity Are Potent Inhibitors of Biotin Protein Ligase
There is a desperate need to develop new antibiotic agents
to combat
the rise of drug-resistant bacteria, such as clinically important <i>Staphylococcus aureus</i>. 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 <i>S. aureus</i>, <i>Escherichia coli</i>, and <i>Homo sapiens</i>. Two potent inhibitors with <i>K</i><sub>i</sub> <
100 nM were identified with antibacterial activity against a panel
of clinical isolates of <i>S. aureus</i> (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