Nature has created a plethora of living organisms. When learning about plants on earth, we can ask botanists; if interested in animal evolution, we can discuss this with zoologists. But to understand tiny invisible natural product molecules beneath the earth, where should we start? Recently, Lihan Zhang and his team at Westlake University's School of Science revealed a global atlas for bacterial aromatic natural products, published inAngewandte Chemie International Edition.

Link: https://doi.org/10.1002/anie.202202286

Natural products—the hidden treasures created by nature—are organic compounds created by animals, plants, and microbes. Indeed, the majority of clinical medicines—such as penicillin, erythromycin, and streptomycin—are derived from natural products. These invisible tiny molecules have attracted significant interest from researchers in broad fields, and the team led by Zhang focuses on polyketides, a class of natural products with extensive structural variety and potent biological activity.

Aromatic polyketides are one of the subfamilies of polyketide natural products exemplified by the essential drugs tetracycline and doxorubicin. "Although researchers have found thousands of aromatic polyketides, many questions still remain to be solved such as how many of them remain to be discovered, and how much of them have we already discovered," Zhang says. A common approach for discovering natural products is to explore the chemical composition in each living organism, but such a reductive approach cannot provide answers to holistic questions. "With the explosive increase in genome sequencing data, we can now provide a bird's-eye view of natural products by analyzing their biosynthetic genes," Zhang adds.

Figure 1. Representative aromatic polyketides reported to date from nature.

To reveal the global molecular landscape of bacterial aromatic polyketides, the team first analyzed the biosynthetic enzymes—a set of enzymes responsible for making natural products. By analyzing biosynthetic enzymes of known, characterized compounds encoded in the producer hosts' genome, they found that an enzyme called Chain Length Factor (CLF) has the highest correlation with the product compound structure. Additionally, a cutoff value of 0.88 for the CLF amino acid identity was established, which can indicate product uniqueness. These findings enabled the researchers to determine the global abundance of aromatic polyketides. In other words, the work provides straightforward answers to two curious questions in the minds of many natural product chemists: How many unique compounds exist on Earth, and where could we find them? The researchers estimated a total of more than 3,000 aromatic polyketides potentially exist on earth, and their result showed that "rare" actinobacteria, in contrast to "common and well-studied"Streptomyces, have a rich potential for the discovery of new natural products.

Figure 2. Global atlas of aromatic polyketides derived from bacteria.

Finally, the team applied this global atlas to excavate novel aromatic polyketides. Among seven strains that possess novel CLF enzymes, two strains produced novel aromatic polyketides. Interestingly, the compound named oryzanaphthopyran, produced by a "rare" actinobacterium Streptacidiphilusspecies, bears a unique tri-cyclic aromatic scaffold that has never been reported from nature. These discoveries illustrated the application of the global atlas for the discovery of natural products.

"Based on the accumulated knowledge of characterized natural products, we improved the accuracy of bioinformatic prediction, and thanks to the sequence big data we created a global atlas of natural products at a molecular resolution for the first time," Zhang says. The team expects that their results can not only accelerate drug discovery from natural products but also inspire the bioengineering of the aromatic polyketides by uncovering the evolutionary mechanism of these natural products in the microbial world. In the future, such a holistic approach in natural products research will become more and more popular, and bioinformatics-supported global atlases can serve as a compass for fully understanding and exploiting nature's treasured molecules.