caa a22 4500 605498229 CHVBK 20210128100545.0 cr unu---uuuuu 210128e20150801xx s 000 0 eng 10.1007/s00253-015-6635-9 doi (NATIONALLICENCE)springer-10.1007/s00253-015-6635-9 Engineered biosynthesis of pimaricin derivatives with improved antifungal activity and reduced cytotoxicity [Elektronische Daten] [Zhen Qi, Qianjin Kang, Chunyan Jiang, Mo Han, Linquan Bai] Pimaricin is an important antifungal antibiotic for antifungal therapy and prevention of mould contamination in the food industry. In this study, three new pimaricin derivatives, 12-decarboxy-12-methyl pimaricin (1), 4,5-desepoxy-12-decarboxy-12-methyl pimaricin (2), and 2-hydro-3-hydroxy-4,5-desepoxy-12-decarboxy-12-methyl pimaricin (3), were generated through the inactivation of P450 monooxygenase gene scnG in Streptomyces chattanoogensis L10. Compared with pimaricin, 1 displayed a twofold increase in antifungal activity against Candida albicans ATCC 14053 and a 4.5-fold decrease in cytotoxicity with erythrocytes, and 2 had comparable antifungal activity and reduced cytotoxicity, whereas 3 showed nearly no antifungal and hemolytic activities. Genetic and biochemical analyses proved that 1 is converted from 2 by P450 monooxygenase ScnD. Therefore, the overexpression of scnD in scnG-null strain eliminated the accumulation of 2 and improved the yield of 1 by 20%. Conversely, scnG/scnD double mutation abolished the production of 1 and improved the yield of 2 to 2.3-fold. These results indicate that the pimaricin derivatives with improved pharmacological properties obtained by genetic engineering can be further developed into antifungal agents for potential clinical application. Springer-Verlag Berlin Heidelberg, 2015 Streptomyces nationallicence Polyene macrolide nationallicence Pimaricin nationallicence Antifungal activity nationallicence Cytotoxicity nationallicence Qi Zhen State Key Laboratory of Microbial Metabolism, and School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, 200240, Shanghai, China aut Kang Qianjin State Key Laboratory of Microbial Metabolism, and School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, 200240, Shanghai, China aut Jiang Chunyan State Key Laboratory of Microbial Metabolism, and School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, 200240, Shanghai, China aut Han Mo State Key Laboratory of Microbial Metabolism, and School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, 200240, Shanghai, China aut Bai Linquan State Key Laboratory of Microbial Metabolism, and School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, 200240, Shanghai, China aut Applied Microbiology and Biotechnology Springer Berlin Heidelberg 99/16(2015-08-01), 6745-6752 0175-7598 99:16<6745 2015 99 253 https://doi.org/10.1007/s00253-015-6635-9 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00253-015-6635-9 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Qi Zhen State Key Laboratory of Microbial Metabolism, and School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, 200240, Shanghai, China aut NATIONALLICENCE 700 1- Kang Qianjin State Key Laboratory of Microbial Metabolism, and School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, 200240, Shanghai, China aut NATIONALLICENCE 700 1- Jiang Chunyan State Key Laboratory of Microbial Metabolism, and School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, 200240, Shanghai, China aut NATIONALLICENCE 700 1- Han Mo State Key Laboratory of Microbial Metabolism, and School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, 200240, Shanghai, China aut NATIONALLICENCE 700 1- Bai Linquan State Key Laboratory of Microbial Metabolism, and School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, 200240, Shanghai, China aut NATIONALLICENCE 773 0- Applied Microbiology and Biotechnology Springer Berlin Heidelberg 99/16(2015-08-01), 6745-6752 0175-7598 99:16<6745 2015 99 253