Co-culture: stimulate the metabolic potential and explore the molecular diversity of natural products from microorganisms

Microbial secondary metabolites have long been considered as potential sources of lead compounds for medicinal use due to their rich chemical diversity and extensive biological activities. However, many biosynthetic gene clusters remain silent under traditional laboratory culture conditions, resulting in repeated isolation of a large number of known compounds. The co-culture strategy simulates the complex ecological environment of microbial life by using an ecology-driven method to activate silent gene clusters of microorganisms and tap their metabolic potential to obtain novel bioactive secondary metabolites. In this review, representative studies from 2017 to 2020 on the discovery of novel bioactive natural products from co-cultured microorganisms are summarized. A series of natural products with diverse and novel structures have been discovered successfully by co-culture strategies, including fungus-fungus, fungus-bacterium, and bacterium-bacterium co-culture approaches. These novel compounds exhibited various bioactivities including extensive antimicrobial activities and potential cytotoxic activities, especially when it came to disparate marine-derived species and cross-species of marine strains and terrestrial strains. It could be concluded that co-culture can be an effective strategy to tap the metabolic potential of microorganisms, particularly for marine-derived species, thus providing diverse molecules for the discovery of lead compounds and drug candidates.