Actinomycetes, enriched with secondary metabolites, have emerged as a resource for drug discovery. These organisms predominantly harbor bioactive compounds such as polyketides, non-ribosomal peptides, aminoglycosides, and terpenes, with polyketides representing the most diverse class. Polyketides are divided into three major categories based on polyketide synthase: type Ⅰ, type Ⅱ, and type Ⅲ, in which type Ⅰ polyketides are most widely distributed and abundant, with macrocyclic lactone compounds serving as their archetypal representatives. Macrocyclic lactone compounds, frequently utilized as antibiotics, anti-cancer agents, immunosuppressants, and antiparasitic agents, hold immense biological significance. This review comments the biosynthetic process of macrolides, and strategies for biosynthesizing actinomycete polyketides are proposed, which encompass genome remodeling, regulatory pathway recombination, combinatorial metabolic engineering, and the modifications of polyketide structures. By knocking out competing gene clusters and superfluous genomic islands, augmenting the supply of precursors, and enhancing precursor supply and lipid stream processing, researchers can obtain genome-minimized and optimized industrial chassis, followed with manipulations such as promoter engineering, regulatory factor engineering, overexpression of the rate-limiting enzyme genes, enhanced substrate transport and tolerance, targeted modifications of the key enzymes, rational design of polyketides, etc. Furthermore, the optimized chassis and biosynthetic gene clusters are integrated to develop robust strains for multi-omics analyses and fermentation process optimization, which can be guided by rapidly developed synthetic biology enabling technologies and artificial intelligence, to develop a high-quality, efficient polyketides biosynthesis system. These advancements can offer robust technical support for the large-scale production of polyketides pharmaceuticals and their derivatives.
