Recent advances in combinatorial biosynthesis for drug discovery

Abstract

Because of extraordinary structural diversity and broad biological activities, natural products have played a significant role in drug discovery. These therapeutically important secondary metabolites are assembled and modified by dedicated biosynthetic pathways in their host living organisms. Traditionally, chemists have attempted to synthesize natural product analogs that are important sources of new drugs. However, the extraordinary structural complexity of natural products sometimes makes it challenging for traditional chemical synthesis, which usually involves multiple steps, harsh conditions, toxic organic solvents, and byproduct wastes. In contrast, combinatorial biosynthesis exploits substrate promiscuity and employs engineered enzymes and pathways to produce novel “unnatural” natural products, substantially expanding the structural diversity of natural products with potential pharmaceutical value. Thus, combinatorial biosynthesis provides an environmentally friendly way to produce natural product analogs. Efficient expression of the combinatorial biosynthetic pathway in genetically tractable heterologous hosts can increase the titer of the compound, eventually resulting in less expensive drugs. In this review, we will discuss three major strategies for combinatorial biosynthesis: 1) precursor-directed biosynthesis; 2) enzyme-level modification, which includes swapping of the entire domains, modules and subunits, site-specific mutagenesis, and directed evolution; 3) pathway-level recombination. Recent examples of combinatorial biosynthesis employing these strategies will also be highlighted in this review.

Accessing Nature’s diversity through metabolic engineering and synthetic biology

“…A reinvigoration of the potential for engineered enzymes and microorganisms to explore foreign biochemical space and discover molecular probes and therapeutics is clear from a number of recent commentaries and reviews 9 , 11 , 41 , 117 . Here, we describe examples from enzyme and pathway engineering to illustrate the successes, promises, and challenges for mining the plant, fungal, and microbial metabolomes to produce natural product-like molecules.…”

Therapeutic cyclic lipopeptides mining from microbes: latest strides and hurdles

“…The extraordinary structural and functional diversity of natural products has enabled their exploitation for assembly and modification. The usage of engineered enzymes and expression of biosynthetic pathways have broadened the scope of developing effective drug analogs (Sun et al 2015). NRPS being a multi-enzyme family, is amenable for combinatorial biosynthesis.…”

Versatile polyketide biosynthesis platform for production of aromatic compounds in yeast

“…Polyketides are a large class of bioactive natural compounds found widely in fungi (type I iterative and type II ), bacteria (mostly type II, but also type I modular and type III) and plants (type III), possessing a variety of biological activities, including antibacterial, anticancer, antifungal, antiviral and many more [8][9][10][11] . As a consequence, polyketides have been, and still are, major leads in drug discovery programs [11][12][13][14] .…”