Improved Synthesis of Biotinol-5'-AMP: Implications for Antibacterial Discovery.
Tieu W, Polyak SW, Paparella AS, Yap MY, Soares da Costa TP, Ng B, Wang G, Lumb R, Bell JM, Turnidge JD, Wilce MC, Booker GW, Abell AD.
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.