title: Selective inhibition of biotin protein ligase from Staphylococcus aureus.
abstract: 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 (K(i) 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.
authors.affiliation: School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia 5005, Australia.
authors.forename: Tatiana P
authors.initials: TP
authors.lastname: Soares da Costa
authors.affiliation: School of Chemistry and Physics, University of Adelaide, Adelaide, South Australia 5005, Australia.
authors.forename: William
authors.initials: W
authors.lastname: Tieu
authors.affiliation: School of Biomedical Science, Monash University, Victoria 3800, Australia.
authors.forename: Min Y
authors.initials: MY
authors.lastname: Yap
authors.affiliation: School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia 5005, Australia; School of Biomedical Science, Monash University, Victoria 3800, Australia.
authors.forename: Nicole R
authors.initials: NR
authors.lastname: Pendini
authors.affiliation: School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia 5005, Australia. Electronic address: steven.polyak@adelaide.edu.au.
authors.forename: Steven W
authors.initials: SW
authors.lastname: Polyak
authors.affiliation: School of Chemistry and Physics, University of Adelaide, Adelaide, South Australia 5005, Australia.
authors.forename: Daniel
authors.initials: D
authors.lastname: Sejer Pedersen
authors.affiliation: School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia 5005, Australia.
authors.forename: Renato
authors.initials: R
authors.lastname: Morona
authors.affiliation: School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia 5005, Australia; SA Pathology at Women's and Children's Hospital, South Australia 5006, Australia.
authors.forename: John D
authors.initials: JD
authors.lastname: Turnidge
authors.affiliation: School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia 5005, Australia.
authors.forename: John C
authors.initials: JC
authors.lastname: Wallace
authors.affiliation: School of Biomedical Science, Monash University, Victoria 3800, Australia.
authors.forename: Matthew C J
authors.initials: MCJ
authors.lastname: Wilce
authors.affiliation: School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia 5005, Australia.
authors.forename: Grant W
authors.initials: GW
authors.lastname: Booker
authors.affiliation: School of Chemistry and Physics, University of Adelaide, Adelaide, South Australia 5005, Australia.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Abell
mesh_terms: D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D001710:Biotin / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D057930:Click Chemistry; D018360:Crystallography, X-Ray; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008025:Ligases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D013211:Staphylococcus aureus / Q000201:enzymology*; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D014230:Triazoles; D001710:Biotin; D008025:Ligases