Methanotrophs as a reservoir for bioactive secondary metabolites: Pitfalls, insights and promises

Methanotrophs are potent natural producers of several bioactive secondary metabolites (SMs) including isoprenoids, polymers, peptides, and vitamins. Cryptic biosynthetic gene clusters identified from these microbes via genome mining hinted at the vast and hidden SM biosynthetic potential of these microbes. Central carbon metabolism in methanotrophs offers rare pathway intermediate pools that could be further diversified using advanced synthetic biology tools to produce valuable SMs; for example, plant polyketides, rare carotenoids, and fatty acid-derived SMs. Recent advances in pathway reconstruction and production of isoprenoids, squalene, ectoine, polyhydroxyalkanoate copolymer, cadaverine, indigo, and shinorine serve as proof-of-concept. This review provides theoretical guidance for developing methanotrophs as microbial chassis for high-value SMs. We summarize the distinct secondary metabolic potentials of type I and type II methanotrophs, with specific attention to products relevant to biomedical applications. This review also includes native and non-native SMs from methanotrophs, their therapeutic potential, strategies to induce silent biosynthetic gene clusters, and challenges.