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Stepwise increase of fidaxomicin in an engineered heterologous host Streptomyces albus through multi-level metabolic

Huang Xie1,2, Yi-Ting Su1,2, Qing-Ting Bu1,2

  • 1First Affiliated Hospital and Institute of Pharmaceutical Biotechnology, Zhejiang University School of Medicine, Hangzhou 310058, China.

Synthetic and Systems Biotechnology
|July 18, 2024
PubMed

Insights

Scientists engineered a new strain for producing fidaxomicin, an antibiotic crucial for treating Clostridium difficile infections. This enhanced strain achieved a 15-fold increase in production yield compared to the original.

Area of Science:

  • Metabolic Engineering
  • Synthetic Biology
  • Antimicrobial Drug Discovery

Background:

  • Fidaxomicin is a critical antibiotic for treating *Clostridium difficile* infections (CDI).
  • It is a natural polyketide metabolite primarily produced by *Micromonosporaceae* species.
  • Current production methods using native strains have limitations in yield and efficiency.

Purpose of the Study:

  • To develop a high-yield heterologous production system for fidaxomicin.
  • To engineer a robust microbial chassis for enhanced fidaxomicin biosynthesis.
  • To establish a combinatorial metabolic engineering strategy for increased drug production.

Main Methods:

  • Utilized a stepwise strategy involving heterologous expression and chassis construction.
  • Implemented promoter engineering, overexpression of activators and transporters.
  • Optimized fermentation media and employed a 5 L-tank bioreactor for scaled production.

Main Results:

  • Achieved a maximum fidaxomicin yield of 384 mg/L using engineered *Streptomyces albus* D7-VHb.
  • Demonstrated a 15-fold increase in yield compared to the native strain *Actinoplanes deccanensis* YP-1.
  • Reported enhanced strain stability and growth rate in the engineered strain.

Conclusions:

  • Successfully developed an enhanced chassis strain for fidaxomicin production.
  • Achieved the first-ever heterologous synthesis of fidaxomicin via a combinatorial metabolic engineering approach.
  • The engineered strain offers a more stable and efficient alternative for fidaxomicin manufacturing.
Keywords:
FidaxomicinGenome-reduced chassisHeterologous expressionMetabolic engineeringStreptomyces albus

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