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Christian P Ridley1, Ho Young Lee, Chaitan Khosla

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Understanding the evolution of polyketide antibiotics and bacterial polyketide synthases (PKSs) is crucial for developing new antimicrobial drugs. This research explores PKS evolution to guide the creation of next-generation antibiotics.

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Area of Science:

  • Biochemistry and Molecular Biology
  • Evolutionary Biology
  • Drug Discovery

Background:

  • Rising antibiotic resistance in human pathogens necessitates novel therapeutic agents.
  • Polyketides are a class of natural products with demonstrated antimicrobial properties.
  • Bacterial polyketide synthases (PKSs) are key enzymes responsible for polyketide biosynthesis.

Purpose of the Study:

  • To investigate the evolutionary pathways that led to the diverse chemistry of modern PKSs.
  • To understand how PKSs gain new metabolic functions.
  • To provide insights for biosynthetic engineers aiming to create novel polyketide antibiotics.

Main Methods:

  • Phylogenetic analysis of PKS gene families.
  • Structural analysis of PKS enzymes.
  • Comparative genomics and evolutionary modeling.

Main Results:

  • Identified key evolutionary events driving PKS diversification.
  • Elucidated mechanisms of PKS domain evolution and horizontal gene transfer.
  • Correlated structural features with functional innovations in PKS.

Conclusions:

  • The diverse chemical repertoire of PKSs evolved through a combination of gene duplication, domain shuffling, and acquisition of new catalytic modules.
  • Understanding PKS evolution provides a roadmap for rational design of engineered PKSs.
  • This knowledge is vital for the future development of novel polyketide-based antimicrobials to combat resistance.