Evolutionary strategies of late-stage diversification in bacterial biosynthetic gene clusters

Natural products are complex chemical molecules produced by organisms to carry out a wide range of functions. The remarkable chemical diversity of these compounds arises from the diversity of the biosynthetic gene clusters (BGCs) that encode the enzymes responsible for their biosynthesis. In the present mini-review, we explore the processes that drive late-stage diversification of BGCs, where small changes generate highly similar yet distinct compounds. We consider examples of non-modular and modular BGCs and discuss the mechanisms behind their diversification, such as enzyme promiscuity, point mutations, and recombination. Then, we use a fitness landscape concept borrowed from the field of evolutionary biology to consider how these mechanisms allow BGCs to explore the chemical space of possible molecules and illustrate why recombination is such a powerful mechanism for natural product diversification in modular systems. Lastly, we argue that the framework of fitness landscapes could help understand the expected bioactivity of unknown natural products.