Artificial Recombination of Nonribosomal Peptide Synthetases Rapidly Evolves Natural Products
Zhong, L.; Wang, X.; Shi, X.; Bai, X.; Liu, Y.; Chen, H.; Seenivasan, B.; Ji, X.; Yang, Q.; Li, S.; Mueller, R.; Tu, Q.; Zhang, Y.-M.; Bian, X.
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Efficient engineering of nonribosomal peptide synthetases (NRPSs) is a key strategy for expanding valuable peptide natural products. Current bioinformatics-guided approaches are often constrained by a set of predefined fusion sites, remaining experimentally challenging in most NRPS systems. Here we present the Recombineering Accelerated Evolution (RACE), which harnesses Red/ET recombineering mediated partially matched homologous recombination to recapitulate recombination-driven NRPS evolution on a highly accelerated timescale. Application of RACE to six known NRPS gene clusters generated 830 recombinants and yielded over 600 novel peptides including novel bis-lipopeptides. These recombinants reveal 112 previously unrecognized recombination fusion sites, providing an extensive landscape for NRPS evolution and more useful resources for guiding NRPS engineering. The RACE establishes a new paradigm for programmable NRPS evolution and enables rapid discovery of bioactive peptides.
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