Sahner J Henning, Sucipto Hilda, Wenzel Silke C, Groh Matthias, Hartmann Rolf W, Müller Rolf
Department of Drug Design and Optimization, Helmholtz Institute for Pharmaceutical Research Saarland, Pharmaceutical and Medicinal Chemistry, Saarland University, University Building C2 3, 66123 Saarbrücken (Germany); German Centre for Infection Research (DZIF), Partner Site, Hannover-Braunschweig, University Building C2 3, 66123 Saarbrücken (Germany).
Chembiochem. 2015 Apr 13;16(6):946-53. doi: 10.1002/cbic.201402666. Epub 2015 Mar 10.
Myxopyronin is a natural α-pyrone antibiotic from the soil bacterium Myxococcus fulvus Mx f50. Myxopyronin inhibits bacterial RNA polymerase (RNAP) by binding to a part of the enzyme not targeted by the clinically used rifamycins. This mode of action makes myxopyronins promising molecules for the development of novel broad-spectrum antibacterials. We describe the derivatization of myxopyronins by an advanced mutasynthesis approach as a first step towards this goal. Site-directed mutagenesis of the biosynthetic machinery was used to block myxopyronin biosynthesis at different stages. The resulting mutants were fed with diverse precursors that mimic the biosynthetic intermediates to restore production. Mutasynthon incorporation and production of novel myxopyronin derivatives were analyzed by HPLC-MS/MS. This work sets the stage for accessing numerous myxopyronin derivatives, thus significantly expanding the chemical space of f α-pyrone antibiotics.
粘吡喃菌素是一种从土壤细菌黄色粘球菌Mx f50中提取的天然α-吡喃酮抗生素。粘吡喃菌素通过与临床使用的利福霉素未靶向的酶的一部分结合来抑制细菌RNA聚合酶（RNAP）。这种作用方式使粘吡喃菌素成为开发新型广谱抗菌剂的有前景的分子。我们描述了通过先进的突变合成方法对粘吡喃菌素进行衍生化，作为朝着这一目标迈出的第一步。利用生物合成机制的定点诱变在不同阶段阻断粘吡喃菌素的生物合成。给所得突变体投喂模拟生物合成中间体的各种前体以恢复生产。通过HPLC-MS/MS分析新型粘吡喃菌素衍生物的突变合成子掺入和生产情况。这项工作为获取众多粘吡喃菌素衍生物奠定了基础，从而显著扩展了α-吡喃酮抗生素的化学空间。
