Recent advances in natural product discovery

Abstract

Natural products have been and continue to be the source and inspiration for a substantial fraction of human therapeutics. Although the pharmaceutical industry has largely turned its back on natural product discovery efforts, such efforts continue to flourish in academia with promising results. Natural products have traditionally been identified from a top-down perspective, but more recently genomics- and bioinformatics-guided bottom-up approaches have provided powerful alternative strategies. Here we review recent advances in natural product discovery from both angles, including diverse sampling and innovative culturing and screening approaches, as well as genomics-driven discovery and genetic manipulation techniques for both native and heterologous expression.

Figure 1

Overview of the recent strategies applied in natural product discovery.

Figure 2

The “knock-in” strategy used in Aspergillus nidulans. A. Replacement of the promoters in front of the transcription activators identified three compounds from Aspergillus nidulans. B. Replacement of the promoters in front of the non-reducing PKSs identified eight compounds from Aspergillus nidulans.

Figure 3

The plug-and-play scaffold developed for cryptic pathway activation and mechanistic study. The whole gene cluster was refactored by inserting constitutive promoters in front of each gene involved in the PTM biosynthesis pathway. Single-deletion and multiple-deletion constructs were assembled to elucidate the biosynthetic steps.