New ways to obtain elusive natural products are reported in two studies published online this week in Nature Chemical Biology. These small molecules are particularly important as they often play a central role in drug discovery efforts, either by serving directly as drugs or lead compounds, or by providing new chemical scaffolds.
Some natural products have evolved as a response to a particular ecological cue, such as the presence of an enemy or adverse weather conditions. As a result, the compounds are not typically produced in laboratory environments.
Two papers describe methods to find these compounds by manipulating or reading the genes that encode them. Joern Piel and colleagues tackled the complicated system of interacting symbionts in sea sponges. Because the bacteria often depend on the sponge for growth, and many kinds of bacteria can be housed in a single sponge, characterizing a single bacterium is significantly challenging, if not impossible. The authors used their understanding of the chemical reactions that are required to make the molecules to search for the DNA sequence of a particular type of biosynthetic enzyme the ketosynthases. With the DNA in hand, the authors were able to quickly identify all of the genes needed forcompound synthesis.
In a different approach, Nancy Keller and colleagues were inspired by the discovery that natural products might be regulated by histone modifications, or epigenetic signals. By removing a critical component of a protein complex involved in histone modifications, the authors observed the appearance of several small molecules.
Both strategies should provide general approaches for natural product discovery.