Expanding perspectives on specialized metabolism in Streptomyces bacteria

Streptomyces bacteria are prodigious producers of specialized metabolites, although when, why, and how they make many of these molecules is a puzzle that scientists have been working to solve for decades. While impressive progress has been made, new paradigms continue to be revealed, and new discoveries are increasingly facilitating access to the untapped metabolic potential of these bacteria. Here, we summarize recent advances in the specialized metabolism field that expand our views of what is possible, from regulation, production, and dissemination perspectives. We discuss the interplay between cluster-situated regulators and genes outside their biosynthetic clusters, as well as the intersection of these 'base regulators' with more globally acting pleiotropic regulators and nucleoid-associated proteins. We further describe the competition between different pleiotropic regulators and how this collectively enables the efficient integration of multiple regulatory inputs into biosynthetic gene cluster control. Finally, we highlight the production potential of cell types and growth stages that have not historically been associated with specialized metabolism, and describe intriguing containment strategies for biosynthetic enzymes and for the distribution of their metabolic products.