Novel Synthesis Method to Produce Hybrid Nonribosomal Peptides (NRPs) with Enhanced Diversity and Functionality

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Professor Timothy Lu
Department of Biological Engineering, MIT
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Sara Cleto
Research Laboratory of Electronics, MIT
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Jon Gilbert
MIT Technology Licensing Officer
Patent Protection

Compressed pathways for nonribosomal molecular biosynthesis

PCT Patent Application WO 2016-196940


Nonribosomal peptides (NRPs) are diverse and have a broad range of biological activities and pharmacological properties. For example, they are widely used as pharmaceuticals (e.g., broad-spectrum antibiotics; anti-cancer drugs) and in the agricultural industry as insecticides. The ability to rationally engineer novel, hybrid NRPs will expand the pool of chemical entities available. These entities can potentially be used to combat a variety of infections and diseases.

Problem Addressed

NRPs are a class of peptides produced in microorganisms such as bacteria and fungi. As opposed to ribosome-based synthesis, NRPs are produced by multi-domain complexes called nonribosomal peptide synthetases (NRPSs). NRPSs catalyze the sequential addition of natural and unnatural amino acids into a growing peptide chain. NRPs exhibit a wide range of bioactivities and applications. However, the production of native NRPs is notoriously difficult in a laboratory setting and often delivers a very low product yield. Existing methods of chemical synthesis are similarly impractical or not yet elucidated due to the structural complexity of many NRPs. These drawbacks have led to the use of surrogate hosts (e.g., E. coli) for the heterologous production of NRPs. NRP biosynthesis pathways can be introduced into E. coli in their original form or, alternatively, the pathways can be optimized for bioactivity or product yield. Compressing multiple NRP biosynthesis pathways, as described within, makes it possible to generate non-naturally occurring nonribosomal molecules that exhibit an array of structural and functional diversity with various bioactivities and applications.


This technology is a method to produce a wide range of novel nonribosomal molecules by compressing two existing heterologous biosynthesis pathways and supplementing the growth medium with a precursor. The system is a modified strain of E. coli engineered to express a biosynthetic pathway composed of four components: 1) biosynthetic genes from one species encoding enzymes for the assembly of a nonribosomal molecule, 2) biosynthetic genes from a second species encoding enzymes for the assembly of a different nonribosomal molecule, 3) a gene encoding an amide synthase, and 4) exogenously supplied building blocks. The components of the system are selected based on their potential to endow the hybrid molecule with desired functionalities (e.g., ion chelation; fluorescence; bactericidal or virucidal properties). The two molecule intermediates and one building block molecule are condensed via the aforementioned amide synthase to generate one hybrid nonribosomal molecule. As such, this method allows for the rational design of novel nonribosomal molecules with hybrid functionality not found in a natural environment. 


  • Allows for the production of a diverse range of novel nonribosomal molecules