Unlocking the Therapeutic Potential of Antimicrobial Natural Products with Synthetic Biology

Although once a mainstay of drug discovery efforts within the pharmaceutical industry, enthusiasm for the use of natural products as a starting point for the development of new medicines has steadily declined since the early 1990s. As a consequence, many companies have opted to jettison their natural product screening programs in favor of high-throughput synthesis and combinatorial chemistry, approaches that have ultimately failed to deliver on their early promise. Yet despite their deprioritization, > 60% of all small molecule drugs in current clinical use can trace their origins back to natural product scaffolds. There is now an increasing realization that these privileged structures represent the optimal starting point for the development of clinically viable assets. Here, we outline the current state-of-the-art in antimicrobial natural product drug discovery, with a specific focus on how the emerging field of synthetic biology is delivering the tools and technologies required to unlock the therapeutic potential of natural products. We illustrate how these approaches are circumventing many of the problems that have historically plagued conventional screening programs, enabling the expedient discovery of new molecules with novel functions, and the design and development of therapeutically optimized ‘unnatural’ natural products.