Synthetic biology to access and expand nature's chemical diversity

Abstract

Bacterial genomes encode the biosynthetic potential to produce hundreds of thousands of complex molecules with diverse applications, from medicine to agriculture and materials. Economically accessing the potential encoded within sequenced genomes promises to reinvigorate waning drug discovery pipelines and provide novel routes to intricate chemicals. This is a tremendous undertaking, as the pathways often comprise dozens of genes spanning as much as 100+ kiliobases of DNA, are controlled by complex regulatory networks, and the most interesting molecules are made by non-model organisms. Advances in synthetic biology address these issues, including DNA construction technologies, genetic parts for precision expression control, synthetic regulatory circuits, computer aided design, and multiplexed genome engineering. Collectively, these technologies are moving towards an era when chemicals can be accessed en mass based on sequence information alone. This will enable the harnessing of metagenomic data and massive strain banks for high-throughput molecular discovery and, ultimately, the ability to forward design pathways to complex chemicals not found in nature.

Natural products and morphogenic activity of γ-Proteobacteria associated with the marine hydroid polyp Hydractinia echinata

“…7 Furthermore, steadily increasing numbers of genome sequencing projects have uncovered, that bacteria in general and marine host-associated bacteria in particular, habor an enormous biosynthetic capacity, which by far exceeds the numbers of currently reported natural products. However, most gene clusters remain “silent” (cryptic) under standard laboratory cultivation conditions, 8 and require the application of optimized heterologous expression systems to enable the identification of the encoded metabolites. Only recently, Moore and co-workers isolated and identified the lipopeptides bromoalterochromide A and B ( 5 – 6 ) 9 by transferring a ∼34 kb secondary metabolite pathway from Pseudoalteromonas piscicida JCM 20779 into E. coli as the expression host.…”

De novo Biosynthesis of “Non‐Natural” Thaxtomin Phytotoxins

“…However there are many microorganisms that produce useful secondary metabolites, which are not amenable to such genetic manipulation. The rise of synthetic biology has provided access to larger synthetic DNA constructs, rapid DNA capture,7, 8, 9 editing,10, 11 assembly,12, 13 and other advances 14, 15. The prospect of using these new tools to assemble de novo biosynthetic pathways in well‐characterized heterologous host strains16, 17 for diversification and optimization of natural products, derived from less tractable microorganisms, is an attractive goal.…”

Future therapeutics through synthetic biology

“…Synthetic biology has positioned itself capable of doing what synthetic organic chemistry did to change the scientific landscape a century ago (Yeh and Lim, 2007;Smansk et al, 2016). Organic synthesis, in spite of many notable advances, especially in the synthesis of prevalent Natural Product (NP) backbones containing fiveand six-membered ring compounds (Nicolaou, 2014;Piers and Karunaratne, 1983;Posner, 1986), has not become the panacea for the production of NPs for the pharmaceutical industry.…”