Although natural products and synthetic small molecules both serve important medicinal functions, their structures and chemical properties are relatively distinct. To expand the molecular diversity available for drug discovery, one strategy is to blend the effective attributes of synthetic and natural molecules. A key feature found in synthetic compounds that is rare in nature is the use of fluorine to tune drug behavior. We now report a method to site-selectively incorporate fluorine into complex structures to produce regioselectively fluorinated full-length polyketides. We engineered a fluorine-selective trans-acyltransferase to produce site-selectively fluorinated erythromycin precursors in vitro. We further demonstrated that these analogs could be produced in vivo in Escherichia coli on engineering of the fluorinated extender unit pool. By using engineered microbes, elaborate fluorinated compounds can be produced by fermentation, offering the potential for expanding the identification and development of bioactive fluorinated small molecules.

尽管天然产物和合成小分子都具有重要的药用功能，但它们的结构和化学性质相对不同。为了扩大可用于药物发现的分子多样性，一种策略是融合合成分子和天然分子的有效属性。合成化合物的一个在自然界中罕见的关键特征是使用氟来调节药物行为。我们现在报告了一种将氟选择性地结合到复杂结构中以产生区域选择性氟化全长聚酮化合物的方法。我们设计了一种氟选择性反酰基转移酶，以在体外产生位点选择性氟化红霉素前体。我们进一步证明，通过氟化增量剂单元库的工程设计，这些类似物可以在大肠杆菌体内产生。通过使用工程微生物，可以通过发酵生产精细的氟化化合物，为扩大生物活性氟化小分子的识别和开发提供了潜力。