Biotin analogues with antibacterial activity are potent inhibitors of biotin protein ligase

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: antibiotic; biotin protein ligase; enzyme; enzyme inhibitor; medicinal chemistry.

Figure 1

Chemical structures of (a) biotin 1 and its analogues (b) α-dehydrobiotin, (c) N1 substituted biotin, and (d) the pharmacophore investigated in this study.

Figure 2

X-ray structures of inhibitors in complex with BPL. S. aureus BPL was crystallized in complex with biotin analogues alcohol 6 (a) and acetylene 14 (b). The hydrogen-bonding interactions with the inhibitors are shown.

Scheme 1

Figure 3

SPR analysis of BPL inhibitor binding. Surface plasmon resonance sensorgrams are shown for the binding of (a) biotin, (b) 6, (c) 16, and (d) 5 to immobilized S. aureus BPL. Varying concentrations of the inhibitors were included in the running buffer, and analysis was performed as described in the Supporting Information.