[Advances in metabolic engineering of macrolide antibiotics]
1National Health Commission Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing 100050, China.
Abstract:
14- to 16-membered macrolide antibiotics (MA) are clinically important anti-infective drugs. With the rapid emergence of bacterial resistance, there is an urgent need to develop novel MA to counter drug-resistant bacteria. The targeted optimization of MA can be guided by analyzing the interaction between the MA and its ribosomal targets, and the desired MA derivatives can be obtained efficiently when combining with the rapidly developed metabolic engineering approaches. In the past 30 years, metabolic engineering approaches have shown great advantages in engineering the biosynthesis of MA to create new derivatives and to improve their production. These metabolic engineering approaches include modification of the structural domains of the polyketide synthase (PKS) and post-PKS modification enzymes as well as combinatorial biosynthesis. In addition, the R&D (including the evaluation of its antimicrobial activities and the optimization through metabolic engineering) of carrimycin, a new 16-membered macrolide drug, are described in details in this review.
Insights
Novel macrolide antibiotics (MA) are crucial for combating bacterial resistance. Metabolic engineering offers powerful strategies to develop new MA derivatives and enhance their production by modifying biosynthesis pathways.
Area of Science:
- Microbiology
- Biotechnology
- Medicinal Chemistry
Background:
- 14- to 16-membered macrolide antibiotics (MA) are vital anti-infective agents.
- Emerging bacterial resistance necessitates the development of novel MA.
- Understanding MA-ribosomal target interactions guides rational drug design.
Purpose of the Study:
- To review the application of metabolic engineering in developing novel macrolide antibiotics.
- To highlight strategies for creating new MA derivatives and improving production.
- To detail the research and development of carrimycin, a 16-membered macrolide.
Main Methods:
- Modification of polyketide synthase (PKS) structural domains.
- Engineering of post-PKS modification enzymes.
- Application of combinatorial biosynthesis and metabolic engineering.
Main Results:
- Metabolic engineering has proven effective in creating novel MA derivatives over 30 years.
- These approaches enhance the production of existing and new macrolide antibiotics.
- Carrimycin development showcases successful optimization through metabolic engineering.
Conclusions:
- Metabolic engineering is a key strategy for developing next-generation macrolide antibiotics.
- Targeted optimization of MA biosynthesis pathways can overcome bacterial resistance.
- Continued research in metabolic engineering is essential for novel anti-infective drug discovery.
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