Improved Synthesis of Biotinol-5'-AMP: Implications for Antibacterial Discovery

William Tieu; Steven W Polyak; Ashleigh S Paparella; Min Y Yap; Tatiana P Soares da Costa; Belinda Ng; Geqing Wang; Richard Lumb; Jan M Bell; John D Turnidge; Matthew C J Wilce; Grant W Booker; Andrew D Abell

doi:10.1021/ml500475n

Improved Synthesis of Biotinol-5'-AMP: Implications for Antibacterial Discovery

ACS Med Chem Lett. 2014 Dec 11;6(2):216-20. doi: 10.1021/ml500475n. eCollection 2015 Feb 12.

Authors

Affiliations

¹ School of Chemistry and Physics, University of Adelaide , Adelaide, South Australia 5005, Australia ; Centre for Molecular Pathology, The University of Adelaide , Adelaide, South Australia 5005, Australia.
² School of Molecular and Biomedical Science, University of Adelaide , Adelaide, South Australia 5005, Australia ; Centre for Molecular Pathology, The University of Adelaide , Adelaide, South Australia 5005, Australia.
³ School of Molecular and Biomedical Science, University of Adelaide , Adelaide, South Australia 5005, Australia.
⁴ School of Biomedical Science, Monash University , Victoria 3800, Australia.
⁵ Microbiology and Infectious Diseases Directorate, SA Pathology, Women's and Children's Hospital , Adelaide, South Australia 5006, Australia.
⁶ School of Molecular and Biomedical Science, University of Adelaide , Adelaide, South Australia 5005, Australia ; Microbiology and Infectious Diseases Directorate, SA Pathology, Women's and Children's Hospital , Adelaide, South Australia 5006, Australia.

Abstract

An improved synthesis of biotinol-5'-AMP, an acyl-AMP mimic of the natural reaction intermediate of biotin protein ligase (BPL), is reported. This compound was shown to be a pan inhibitor of BPLs from a series of clinically important bacteria, particularly Staphylococcus aureus and Mycobacterium tuberculosis, and kinetic analysis revealed it to be competitive against the substrate biotin. Biotinol-5'-AMP also exhibits antibacterial activity against a panel of clinical isolates of S. aureus and M. tuberculosis with MIC values of 1-8 and 0.5-2.5 μg/mL, respectively, while being devoid of cytotoxicity to human HepG2 cells.

Keywords: Antibiotics; biotin protein ligase; chemical synthesis; drug design; enzyme inhibitors.