A Natural Product Chemist's Guide to Unlocking Silent Biosynthetic Gene Clusters

Brett C. Covington, Fei Xu, Mohammad R. Seyedsayamdost

Research output: Contribution to journalReview articlepeer-review

48 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)763-788
Number of pages26
JournalAnnual review of biochemistry
StatePublished - Jun 20 2021

All Science Journal Classification (ASJC) codes

  • Biochemistry


  • Bacteria
  • Biosynthesis
  • Cryptic metabolite
  • Natural product
  • Silent gene cluster


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