Department of Chemistry, Princeton University, Princeton, New Jersey 08544, USA; email:
Institute of Pharmaceutical Biotechnology and Department of Gastroenterology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; email:
Annu Rev Biochem. 2021 Jun 20;90:763-788. doi: 10.1146/annurev-biochem-081420-102432. Epub 2021 Apr 13.
Microbial natural products have provided an important source of therapeutic leads and motivated research and innovation in diverse scientific disciplines. In recent years, it has become evident that bacteria harbor a large, hidden reservoir of potential natural products in the form of silent or cryptic biosynthetic gene clusters (BGCs). These can be readily identified in microbial genome sequences but do not give rise to detectable levels of a natural product. Herein, we provide a useful organizational framework for the various methods that have been implemented for interrogating silent BGCs. We divide all available approaches into four categories. The first three are endogenous strategies that utilize the native host in conjunction with classical genetics, chemical genetics, or different culture modalities. The last category comprises expression of the entire BGC in a heterologous host. For each category, we describe the rationale, recent applications, and associated advantages and limitations.
微生物天然产物为治疗靶点提供了重要来源，并激发了各个科学领域的研究和创新。近年来，人们已经清楚地认识到，细菌以沉默或隐藏的生物合成基因簇（BGCs）的形式蕴藏着大量潜在的天然产物。这些 BGCs 可以很容易地在微生物基因组序列中识别出来，但不会产生可检测水平的天然产物。在此，我们为已用于研究沉默 BGCs 的各种方法提供了一个有用的组织框架。我们将所有可用的方法分为四类。前三种是利用天然宿主结合经典遗传学、化学遗传学或不同培养方式的内源性策略。最后一类包括在异源宿主中表达整个 BGC。对于每一类，我们描述了其基本原理、最新应用以及相关的优点和局限性。
