Selective inhibition of Biotin Protein Ligase from Staphylococcus aureus

• Published in: The Journal of biological chemistry 2012-05, Vol.287 (21), p.17823-17832
• Main Authors: Soares da Costa, Tatiana P., Tieu, William, Yap, Min Y., Pendini, Nicole R., Polyak, Steven W., Sejer Pedersen, Daniel, Morona, Renato, Turnidge, John D., Wallace, John C., Wilce, Matthew C.J., Booker, Grant W., Abell, Andrew D.
• Format: Article
• Language: English
• Subjects: Antibiotics; Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - chemistry; Bacterial Proteins - metabolism; Biotin; Biotin - chemistry; Biotin - pharmacology; Biotin Protein Ligase; Cell Line; Click Chemistry; Crystallography, X-Ray; Drug Resistance, Bacterial - drug effects; Enzyme Inhibitors; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzymology; Humans; Ligases - antagonists & inhibitors; Ligases - chemistry; Ligases - metabolism; Medicinal Chemistry; Protein Binding; Staphylococcus aureus - enzymology; Triazoles - chemical synthesis; Triazoles - chemistry; Triazoles - pharmacokinetics; X-ray Crystallography
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.356576

There is a well documented need to replenish the antibiotic pipeline with new agents to combat the rise of drug resistant bacteria. One strategy to combat resistance is to discover new chemical classes immune to current resistance mechanisms that inhibit essential metabolic enzymes. Many of the obvious drug targets that have no homologous isozyme in the human host have now been investigated. Bacterial drug targets that have a closely related human homologue represent a new frontier in antibiotic discovery. However, to avoid potential toxicity to the host, these inhibitors must have very high selectivity for the bacterial enzyme over the human homolog. We have demonstrated that the essential enzyme biotin protein ligase (BPL) from the clinically important pathogen Staphylococcus aureus could be selectively inhibited. Linking biotin to adenosine via a 1,2,3 triazole yielded the first BPL inhibitor selective for S. aureus BPL over the human equivalent. The synthesis of new biotin 1,2,3-triazole analogues using click chemistry yielded our most potent structure (Ki 90 nm) with a >1100-fold selectivity for the S. aureus BPL over the human homologue. X-ray crystallography confirmed the mechanism of inhibitor binding. Importantly, the inhibitor showed cytotoxicity against S. aureus but not cultured mammalian cells. The biotin 1,2,3-triazole provides a novel pharmacophore for future medicinal chemistry programs to develop this new antibiotic class. Inhibitors of biotin protein ligase potentially represent a new antibiotic class. Biotin triazoles inhibit the BPL from Staphylococcus aureus but not the human homologue. Our most potent inhibitor shows cytotoxicity against S. aureus but not cultured mammalian cells. This is the first report demonstrating selective inhibition of BPL.