Journal of the American Chemical Society, Vol.138, No.22, 6968-6971, 2016
Total Synthesis of Circular Bacteriocins by Butelase 1
Circular bacteriocins, ranging from 35 to 70 amino acids, are the largest cyclic peptides produced by lactic acid bacteria to suppress growth of other bacteria. Their end-to-end cyclized backbone that enhances molecular stability is an advantage to survive in pasteurization and cooking processes in food preservation, but becomes a disadvantage and challenge in chemical synthesis. They also contain unusually tong and; highly hydrophobic segments which pose an additional synthetic challenge. Here we report the total synthesis of the three largest circular bacteriocins, AS-48, uberolysin, and garvicin ML, by an efficient chemo enzymatic strategy. A key feature of our synthetic scheme is the use of an Asn-specific butelase-mediated cyclization of their linear precursors, prepared by microwave stepwise synthesis. Antimicrobial assays showed-that the AS-48 linear precursor is inactive at concentrations up to 100 mu M, whereas the macrocyclic AS-48 is potently active against pathogenic and drug-resistant bacteria,with minimal inhibitory concentrations in a sub-micromolar range.