Recent advances in the discovery and combinatorial biosynthesis of microbial 14-membered macrolides and macrolactones.

Macrolides, especially 14-membered macrolides, are a valuable group of antibiotics that originate from various microorganisms. In addition to their antibacterial activity, newly discovered 14-membered macrolides exhibit other therapeutic potentials, such as anti-proliferative and anti-protistal activities. Combinatorial biosynthetic approaches will allow us to create structurally diversified macrolide analogs, which are especially important during the emerging post-antibiotic era. This review focuses on recent advances in the discovery of new 14-membered macrolides (also including macrolactones) from microorganisms and the current status of combinatorial biosynthetic approaches, including polyketide synthase (PKS) and post-PKS tailoring pathways, and metabolic engineering for improved production together with heterologous production of 14-membered macrolides.