Control of the polymyxin analog ratio by domain swapping in the nonribosomal peptide synthetase of Paenibacillus polymyxa
| Autor: | Qiu-Man Xu, Jing-Sheng Cheng, Si-Cen Yu, Ying-Jin Yuan, Ye Yuan, Hui-Zhong Sun |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Polymyxin B1 medicine.drug_class Polymyxin 030106 microbiology Bioengineering Applied Microbiology and Biotechnology Condensation domain 03 medical and health sciences chemistry.chemical_compound Lipopeptides Surface-Active Agents Nonribosomal peptide Drug Resistance Multiple Bacterial Gene cluster medicine Polymyxins Peptide Synthases Adenylylation chemistry.chemical_classification biology Lipopeptide biology.organism_classification Anti-Bacterial Agents Culture Media Agar 030104 developmental biology chemistry Biochemistry Metabolic Engineering Fermentation Paenibacillus polymyxa Biotechnology |
| Zdroj: | Journal of industrial microbiologybiotechnology. 47(6-7) |
| ISSN: | 1476-5535 |
| Popis: | Polymyxins are used as the last-line therapy against multidrug-resistant bacteria. However, their further clinical development needs to solve problems related to the presence of heterogeneous analogs, but there is still no platform or methods that can regulate the biosynthesis of polymyxin analogs. In this study, we present an approach to swap domains in the polymyxin gene cluster to regulate the production of different analogs. Following adenylation domain swapping, the proportion of polymyxin B1 increased from 41.36 to 52.90%, while that of B1-1 decreased from 18.25 to 3.09%. The ratio of polymyxin B1 and B3 following starter condensation domain swapping changed from 41.36 and 16.99 to 55.03 and 6.39%, respectively. The two domain-swapping strains produced 62.96% of polymyxin B1, 6.70% of B3 and 3.32% of B1-1. This study also revealed the presence of overflow fluxes between acetoin, 2,3-butanediol and polymyxin. To our best knowledge, this is the first report of engineering the polymyxin synthetase gene cluster in situ to regulate the relative proportions of polymyxin analogs. This research paves a way for regulating lipopeptide analogs and will facilitate the development of novel lipopeptide derivatives. |
| Databáze: | OpenAIRE |
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