Structural Diversification of 14-Membered Macrolides by Chemoenzymatic Synthesis
Brian J Curtis1, Hannah A Boesger1,2, Jennifer J Schmidt1
1Life Sciences Institute, University of Michigan, Mary Sue Coleman Hall, 210 Washtenaw Avenue, Ann Arbor, Michigan 48109-2216, United States.
JACS Au
|February 27, 2026
Summary
Researchers explored the pikromycin polyketide synthase (PKS) system to create novel antibiotic scaffolds. This study efficiently diversified macrolactones and identified new lactones using chemoenzymatic synthesis.
Area of Science:
- Biochemistry
- Organic Chemistry
- Synthetic Biology
Background:
- The pikromycin polyketide synthase (PKS) is known for producing 12- and 14-membered macrolactones.
- Exploring PKS flexibility is crucial for discovering new bioactive compounds.
Purpose of the Study:
- To efficiently diversify novel 14-membered macrolactones using the PikAIII/PikAIV PKS system.
- To identify 6-membered δ-lactones from unnatural pentaketides.
- To investigate the chemoenzymatic synthesis of complex antibiotic scaffolds.
Main Methods:
- Utilized an *in vitro* PikAIII/PikAIV PKS system with unnatural pentaketides.
- Performed D-desosamine addition and late-stage C-H hydroxylation on new macrocycles.
- Employed molecular dynamics (MD) simulations and density functional theory (DFT) calculations.
Main Results:
- Successfully diversified 14-membered macrolactones and identified 6-membered δ-lactones.
- Demonstrated the PikAIII/PikAIV system's ability to process non-native substrates.
- Elucidated the reactivity and selectivity of the terminal catalytic step via computational methods.
Conclusions:
- The PikAIII/PikAIV PKS bimodule system exhibits significant flexibility in processing unnatural substrates.
- Sequential biocatalytic steps are effective for chemoenzymatic synthesis of complex antibiotic scaffolds.
- This approach offers a powerful strategy for generating novel antibiotic diversity.
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