Scientists in the field of natural product research are seeing very high re-discovery rates in recent years. Is it because we humans have exhausted nature's biosynthetic diversity? We performed a bioinformatic analysis aimed at answering this questions, focusing in particular on nonribosomal peptides, the largest family of microbial natural products.
First, our systematic analysis shows that the NRP biosynthetic landscape is uneven. Phenylglycine and its derivatives as a group of NRP building blocks (BBs), for example, have been oversampled, reflecting an extensive historical interest in the glycopeptide antibiotics family. In contrast, the benzoyl BB, including 2,3-dihydroxybenzoate (DHB), has been the most underexplored, hinting at the possibility of a reservoir of as yet unknown DHB containing NRPs with functional roles other than a siderophore. Our results also suggest that there is still vast unexplored biosynthetic diversity in nature, and the analysis presented herein shall help guide and strategize future natural product discovery campaigns. Finally, we discussed possible ways bioinformaticians and biochemists could work together to improve the existing prediction algorithms.