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Gene editing enables rapid engineering of complex antibiotic assembly lines
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Journal Article
Gene editing enables rapid engineering of complex antibiotic assembly lines
2021
Overview
Re-engineering biosynthetic assembly lines, including nonribosomal peptide synthetases (NRPS) and related megasynthase enzymes, is a powerful route to new antibiotics and other bioactive natural products that are too complex for chemical synthesis. However, engineering megasynthases is very challenging using current methods. Here, we describe how CRISPR-Cas9 gene editing can be exploited to rapidly engineer one of the most complex megasynthase assembly lines in nature, the 2.0 MDa NRPS enzymes that deliver the lipopeptide antibiotic enduracidin. Gene editing was used to exchange subdomains within the NRPS, altering substrate selectivity, leading to ten new lipopeptide variants in good yields. In contrast, attempts to engineer the same NRPS using a conventional homologous recombination-mediated gene knockout and complementation approach resulted in only traces of new enduracidin variants. In addition to exchanging subdomains within the enduracidin NRPS, subdomains from a range of NRPS enzymes of diverse bacterial origins were also successfully utilized.
Engineering biosynthetic assembly lines is a powerful path to new natural products but is challenging with current methods. Here the authors use CRISPR-Cas9 to exchange subdomains within NRPS to alter substrate selectivity.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 140/58
/ 38/23
/ 42/41
/ 42/44
/ 45/22
/ 45/23
/ Anti-Bacterial Agents - biosynthesis
/ Anti-Bacterial Agents - chemistry
/ CRISPR
/ Enzymes
/ Homology
/ Humanities and Social Sciences
/ Multienzyme Complexes - chemistry
/ Multienzyme Complexes - genetics
/ Multienzyme Complexes - metabolism
/ Mutation
/ Peptide Synthases - chemistry
/ Peptide Synthases - genetics
/ Peptide Synthases - metabolism
/ Peptides, Cyclic - biosynthesis
/ Peptides, Cyclic - chemistry
/ Science
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