Engineering actinomycetes for biosynthesis of macrolactone polyketides.

Area of Science:

• Microbiology
• Biochemistry
• Synthetic Biology

Background:

• Actinobacteria are prolific natural product (NP) producers with significant pharmaceutical applications.
• Biosynthetic gene clusters (BGCs), often involving polyketide synthases (PKS) or non-ribosomal peptide synthases (NRPS), direct NP production.
• Macrolides, a class of NPs with diverse therapeutic uses, feature a macro-lactone ring synthesized by PKS enzymes.

Purpose of the Study:

• To review versatile strategies for engineering PKS and post-PKS pathways in actinobacteria.
• To explore methods for generating diverse macrolide structures and novel derivatives.
• To discuss approaches for enhancing macrolide production at industrial scales.

Main Methods:

• Genetic and metabolic engineering of actinobacteria.
• Enzyme-level and cellular-level engineering of PKS and post-PKS cascades.
• Application of chemical and biological strategies for macrolide synthesis.

Main Results:

• Engineering PKS and post-PKS pathways allows for the generation of a wide array of macrolide structures.
• These engineered pathways facilitate the production of novel macrolide derivatives with improved biological properties.
• Strategies discussed enable scalable production of macrolides in both native and heterologous actinobacterial hosts.

Conclusions:

• Precise engineering of actinobacterial PKS and post-PKS systems is key to unlocking macrolide diversity.
• Tailored genetic and metabolic modifications can lead to the development of new macrolide-based therapeutics.
• The reviewed approaches provide a framework for industrial-scale macrolide production and derivatization.