Biosynthesis of merochlorins - A novel class of highly active halogenated polyketide antibiotics from marine Streptomyces sp.

海洋微生物最近成为化学上独特的抗菌剂的重要来源，在治疗传染病或癌症方面具有潜在的医学应用。大量的此类化合物是利用芳香聚酮框架进行专门的氧化裁剪反应合成的，这极大地促进了化合物的有效生物活性。最近，一些海洋链霉菌被证明可以产生一类独特的高活性的氯化聚酮抗生素（二氯代），这种抗生素可能来源于戊酰化和卤化四羟基萘前体。依赖钒的氯过氧化物酶可能催化了关键的环化和环扩张步骤。本研究旨在研究新型氯代抗生素的生物合成。该项目的主要重点在于探索导致改性四羟基萘前体的生化步骤，以及对提出的前所未有的氯过氧化物酶催化的大环化和成环/扩张反应的检查。系统的基因失活、外源蛋白及其催化特性的体外研究、定点诱变和x射线晶体学将被应用于相关蛋白的功能分配和表征，并揭示潜在的反应机制，最终目标是建立生物合成管道，用于抗生素筛选的生物学评价。

Marine microbes have recently emerged as an important source of chemically distinct antimicrobial agents with potential for medical applications in the treatment of infectious diseases or cancer. A plenitude of such compounds is synthesized by use of aromatic polyketide frameworks undergoing dedicated oxidative tailoring reactions, which strongly contribute to the compounds potent biological activities. Recently, some marine Streptomyces sp. were shown to produce a unique class of highly active, chlorinated polyketide antibiotics (merochlorins) that may be derived from prenylated and halogenated tetrahydroxynaphthalene precursors. Vanadium-dependent chloroperoxidases presumably catalyze the crucial cyclization and ring-expansion steps. This study aims at investigating the biosynthesis of the novel merochlorin antibiotics. The main focus of the project lies on the exploration of the biochemical steps leading to the modified tetrahydroxynaphthalene precursors, along with the examination of the proposed unprecedented chloroperoxidase-catalyzed macrocyclization and ring-formation/expansion reactions. Systematic gene inactivation, in vitro studies of heterologous proteins and their catalytic features, site-directed mutagenesis, and X-ray crystallography will be applied to functionally assign and characterize involved proteins and to expose the underlying reaction mechanisms, with the ultimate goal to establish biosynthetic pipelines for biological evaluation in antibiotic screens.