Opinion: Hijacking exogenous signals to generate new secondary metabolites during symbiotic interactions

The biosynthesis of secondary metabolites by 'group effort'-in which two or more species cooperate to generate a hybrid small molecule-has been vastly underappreciated. In the laboratory, biosynthetic studies typically focus on a single species that is responsible for the expression of the necessary enzymes and assembly of the small-molecule product. However, in natural environments, microorganisms live in tight associations and are surrounded by a dynamic and intricate exchange of small molecules. The biosynthetic paradigm that is emerging for these conditions is one in which exogenous signals can act as inducers of silent pathways or as alternative substrates that give rise to hybrid small molecules. Examples of such secondary metabolites of dual origin are highlighted in this Perspective article. Aside from demonstrating the remarkable metabolic economy that microorganisms use to create complex molecules, these examples also highlight the benefits of studying biosynthesis using a multispecies approach. This integrative mindset reveals not only the chemistry that underlies symbiotic biosynthetic pathways but also the naturally evolved functions of secondary metabolites that mediate or modulate interspecies interactions.