Streptomyces as a versatile host platform for heterologous production of microbial natural products

Abstract

The rediscovery of natural products (NPs) as a critical source of new therapeutics has been greatly advanced by the development of heterologous expression platforms for biosynthetic gene clusters (BGCs). Among these, Streptomyces species have emerged as the most widely used and versatile chassis for expressing complex BGCs from diverse microbial origins. In this review, we provide a comprehensive analysis of over 450 peer-reviewed studies published between 2004 and 2024 that describe the heterologous expression of BGCs in Streptomyces hosts. We present a data-driven overview of expression trends across time, BGC types, donor species, and host strain preferences, offering the first quantitative perspective on how this field has evolved over two decades. Our review discusses the key factors influencing successful BGC expression in Streptomyces, including genomic integration strategies, regulatory elements, codon optimization, and precursor supply. We also examine the impact of synthetic biology tools, genome engineering, and host strain tailoring in overcoming common expression barriers. Special emphasis is placed on the role of heterologous expression in accessing silent or cryptic BGCs, elucidating biosynthetic pathways, and generating new-to-nature analogues through combinatorial biosynthesis. By integrating technological advances with practical case studies, we highlight how Streptomyces-based heterologous expression is enabling not only the efficient production of known compounds but also the discovery of structurally novel and biologically potent metabolites. This review aims to serve as a resource for researchers in natural products, synthetic biology, and drug discovery who seek to harness the full potential of microbial biosynthetic diversity.