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Control of the polymyxin analog ratio by domain swapping in the nonribosomal peptide synthetase of Paenibacillus polymyxa.
J Ind Microbiol Biotechnol. 2020 Jul; 47(6-7):551-562.JI

Abstract

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.

Authors+Show Affiliations

Frontiers Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), School of Chemical Engineering and Technology, Tianjin University, Yaguan Road 135, Jinnan District, Tianjin, 300350, People's Republic of China. SynBio Research Platform, Collaborative Innovation Centre of Chemical Science and Engineering (Tianjin), School of Chemical Engineering and Technology, Tianjin University, Yaguan Road 135, Jinnan District, Tianjin, 300350, People's Republic of China.Tianjin Key Laboratory of Animal and Plant Resistance, College of Life Science, Tianjin Normal University, Binshuixi Road 393, Xiqing District, Tianjin, 300387, People's Republic of China. qmxu0929@126.com.Frontiers Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), School of Chemical Engineering and Technology, Tianjin University, Yaguan Road 135, Jinnan District, Tianjin, 300350, People's Republic of China.Frontiers Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), School of Chemical Engineering and Technology, Tianjin University, Yaguan Road 135, Jinnan District, Tianjin, 300350, People's Republic of China. SynBio Research Platform, Collaborative Innovation Centre of Chemical Science and Engineering (Tianjin), School of Chemical Engineering and Technology, Tianjin University, Yaguan Road 135, Jinnan District, Tianjin, 300350, People's Republic of China.Frontiers Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), School of Chemical Engineering and Technology, Tianjin University, Yaguan Road 135, Jinnan District, Tianjin, 300350, People's Republic of China. jscheng@tju.edu.cn. SynBio Research Platform, Collaborative Innovation Centre of Chemical Science and Engineering (Tianjin), School of Chemical Engineering and Technology, Tianjin University, Yaguan Road 135, Jinnan District, Tianjin, 300350, People's Republic of China. jscheng@tju.edu.cn.Frontiers Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), School of Chemical Engineering and Technology, Tianjin University, Yaguan Road 135, Jinnan District, Tianjin, 300350, People's Republic of China. SynBio Research Platform, Collaborative Innovation Centre of Chemical Science and Engineering (Tianjin), School of Chemical Engineering and Technology, Tianjin University, Yaguan Road 135, Jinnan District, Tianjin, 300350, People's Republic of China.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32495197

Citation

Yuan, Ye, et al. "Control of the Polymyxin Analog Ratio By Domain Swapping in the Nonribosomal Peptide Synthetase of Paenibacillus Polymyxa." Journal of Industrial Microbiology & Biotechnology, vol. 47, no. 6-7, 2020, pp. 551-562.
Yuan Y, Xu QM, Yu SC, et al. Control of the polymyxin analog ratio by domain swapping in the nonribosomal peptide synthetase of Paenibacillus polymyxa. J Ind Microbiol Biotechnol. 2020;47(6-7):551-562.
Yuan, Y., Xu, Q. M., Yu, S. C., Sun, H. Z., Cheng, J. S., & Yuan, Y. J. (2020). Control of the polymyxin analog ratio by domain swapping in the nonribosomal peptide synthetase of Paenibacillus polymyxa. Journal of Industrial Microbiology & Biotechnology, 47(6-7), 551-562. https://doi.org/10.1007/s10295-020-02275-7
Yuan Y, et al. Control of the Polymyxin Analog Ratio By Domain Swapping in the Nonribosomal Peptide Synthetase of Paenibacillus Polymyxa. J Ind Microbiol Biotechnol. 2020;47(6-7):551-562. PubMed PMID: 32495197.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Control of the polymyxin analog ratio by domain swapping in the nonribosomal peptide synthetase of Paenibacillus polymyxa. AU - Yuan,Ye, AU - Xu,Qiu-Man, AU - Yu,Si-Cen, AU - Sun,Hui-Zhong, AU - Cheng,Jing-Sheng, AU - Yuan,Ying-Jin, Y1 - 2020/06/03/ PY - 2020/03/07/received PY - 2020/04/15/accepted PY - 2020/6/5/pubmed PY - 2020/6/5/medline PY - 2020/6/5/entrez KW - Lipopeptide KW - Nonribosomal peptide synthetase KW - Paenibacillus polymyxa KW - Polymyxin analogs KW - Synthetic biology SP - 551 EP - 562 JF - Journal of industrial microbiology & biotechnology JO - J. Ind. Microbiol. Biotechnol. VL - 47 IS - 6-7 N2 - 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. SN - 1476-5535 UR - https://www.unboundmedicine.com/medline/citation/32495197/Control_of_the_polymyxin_analog_ratio_by_domain_swapping_in_the_nonribosomal_peptide_synthetase_of_Paenibacillus_polymyxa L2 - http://dx.doi.org/10.1007/s10295-020-02275-7 DB - PRIME DP - Unbound Medicine ER -
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