Lanthipeptides Chemical Synthesis vs. In Vivo Biosynthesis for Pharmaceutical Production

Lanthipeptides: Chemical Synthesis vs. In Vivo Biosynthesis for Pharmaceutical Production

1.Research Background

The global healthcare industry faces a severe crisis of antibiotic resistance, creating an urgent demand for novel antimicrobial agents. As a unique class of ribosomally synthesized and post-translationally modified peptides, lanthipeptides (lantibiotics) feature characteristic thioether cross-linked lanthionine and methyllanthionine structures. They possess strong antimicrobial activity, high target specificity and protease resistance, showing great potential to replace traditional antibiotics.

The number of identified lanthipeptides has grown rapidly from 26 in 1997 to over 100 by 2015. However, large-scale manufacturing bottlenecks severely restrict their clinical research and commercial application. Traditional extraction from native microbial strains delivers extremely low yields, while two mainstream production routes — chemical synthesis and in vivo biosynthesis — each have distinct pros and cons. So far, there lacks a comprehensive industrial-oriented comparison between these two production strategies.

2.Research Significance

This review systematically compares chemical synthesis and microbial biosynthesis of lanthipeptides, analyzes their technical difficulties, yields, economic efficiency and industrial applicability. The findings clarify the advantages and limitations of each production method, provide practical guidance for selecting manufacturing routes for pharmaceutical-grade lanthipeptides.

It also summarizes feasible optimization strategies to improve product yield, activity and physicochemical properties of lanthipeptides. The work lays a foundation for advancing process scale-up, accelerating clinical transformation and commercialization of lanthipeptide drugs, and further promotes the development of new anti-resistance antimicrobial therapeutics.

3.Research Content

Structural & Classification Analysis Introduce the core structural features, post-translational modifications (PTMs) and four major classes of lanthipeptides based on biosynthetic gene clusters and modifying enzymes. Illustrate the biosynthesis mechanism of precursor peptides, including the function of leader peptides, modification, cleavage and secretion processes.

Study on Chemical Synthesis Technology Explore solid-phase peptide synthesis (SPPS) and liquid-phase synthesis routes for lanthipeptides. Collect lab-scale synthesis data including reaction steps, total yields and raw material costs. Analyze the challenges of stereospecific synthesis of lanthionine rings and various chemically modified analogues. Evaluate the application of chemical synthesis in structure-activity relationship research and analogue development.

Study on In Vivo Biosynthesis & Bioengineering Summarize production performance of lanthipeptides in native microbial strains and heterologous hosts such as Escherichia coli. Sort out multiple optimization approaches: strain engineering, culture medium reformulation, fermentation parameter adjustment, bioreactor optimization and leader peptide modification. Investigate in vivo mutagenesis for improving peptide activity, solubility and production yield.

Economic & Industrial Feasibility Evaluation Compare the production cost, total yield, product purity, scalability and environmental impact of chemical synthesis and biosynthesis. Sort out the current commercial status, market price and clinical progress of typical lanthipeptide products.

4.Research Results

Chemical Synthesis Outcomes Chemical synthesis is flexible for constructing structural analogues and studying structure-activity relationships. However, lanthipeptides with complex PTMs require dozens to over 70 reaction steps. The overall lab yields are extremely low, ranging from 0.003% to 2.5%. Complicated stereochemical control, expensive catalysts and raw materials lead to prohibitive costs for large-scale industrial production. In addition, some unique modified structures of natural lanthipeptides cannot be fully replicated via chemical methods.

In Vivo Biosynthesis Outcomes Biosynthesis can generate lanthipeptides with natural stereoconfiguration and complete post-translational modifications, requiring fewer downstream purification steps. Optimization of native strains and fermentation conditions can greatly increase yields; for example, the yield of epidermin and gallidermin was raised to hundreds of mg/L. Heterologous expression in E. coli further expands production potential. Multiple engineered lanthipeptide variants exhibit enhanced antimicrobial activity, solubility and stability.

Application & Commercial Status Several lanthipeptide derivatives from chemical synthesis and bioengineering have entered preclinical or clinical trials, such as NVB302 and Mutacin 1140. Nisin is already commercially produced as a food preservative, and microbisporicin has realized pilot-scale industrial biosynthesis for therapeutic use. At present, no lanthipeptide has been officially launched as a human therapeutic drug globally.

5.Discussion

Lanthipeptides are promising candidates against multidrug-resistant pathogens, yet their large-scale production remains the core obstacle for industrialization. Chemical synthesis is suitable for laboratory research, analogue screening and small-batch preparation, but it is not economically viable for industrial mass production due to low total yield and high costs.

In vivo biosynthesis is the only realistic solution for large-scale pharmaceutical manufacturing. Further efforts should focus on high-throughput bioprocess optimization, development of robust heterologous expression systems, and engineering strains to reduce product toxicity and improve secretion efficiency.

Combining biosynthetic production with semi-synthetic modification is a promising development direction, which can integrate the advantages of both methods to obtain lanthipeptide derivatives with better pharmacological properties. With continuous breakthroughs in microbial engineering and fermentation technology, lanthipeptides are expected to become an important new class of antimicrobial drugs in the future.

Reference: Ongey E L, Neubauer P. Lanthipeptides: chemical synthesis versus in vivo biosynthesis as tools for pharmaceutical production[J]. Microbial Cell Factories, 2016, 15: 97. https://doi.org/10.1186/s12934-016-0502-y.

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Email:   jennifer@dilunbio.com