Recent advances in the biosynthesis of bacterial hybrid polyketide-non ribosomal peptide natural products

Polyketide synthases (PKSs) and non-ribosomal peptide synthetases (NRPSs) are multi-modular protein complexes responsible for the biosynthesis of numerous structurally diverse and biologically important natural products (NPs), including many clinically relevant antibiotics. Hybrid PKS-NRPS systems integrate the biosynthetic logic of both pathways, enabling the incorporation of acyl-CoA-derived and amino acid-derived building blocks into complex molecular scaffolds. These hybrid molecules often exhibit enhanced bioactivity, targeting pathogens, tumors, or signaling pathways with remarkable specificity. Numerous gene clusters that harbor both NRPS and PKS enzymes have been reported for the biosynthesis of hybrid NRPS-PKS NPs in a wide range of organisms. Understanding PKS-NRPS hybrids not only unveils the evolutionary ingenuity underlying nature's chemical repertoire but also opens the way to designing tailor-made new-to-nature bioactive compounds. As genome mining, bioinformatics, and enzymatic characterization continue to advance, the exploration and engineering of PKS-NRPS hybrid systems lie at the forefront of NP discovery and synthetic biology. While several hybrid PKS-NRPSs originating from other sources, such as fungi, have been comprehensively reviewed, recent examples from bacteria have not been summarized in detail. This review primarily focuses on bacterial hybrid PKS-NRPS NPs reported over the past decade (2015-2025). Here, we discuss their structures, biological relevance, biosynthetic gene clusters, and potential biosynthetic pathways, presenting a comprehensive overview of the domain arrangements and functional diversity within these fascinating systems. We believe this timely summarized work will be helpful in understanding the biosynthetic intricacies of the bacterial hybrid PK-NRP NPs and their potential therapeutic/biotechnological applications in the future.