title: Engineered biosynthesis of pimaricin derivatives with improved antifungal activity and reduced cytotoxicity.
abstract: 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.
authors.affiliation: State Key Laboratory of Microbial Metabolism, and School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Qi
authors.forename: Qianjin
authors.initials: Q
authors.lastname: Kang
authors.forename: Chunyan
authors.initials: C
authors.lastname: Jiang
authors.forename: Mo
authors.initials: M
authors.lastname: Han
authors.forename: Linquan
authors.initials: L
authors.lastname: Bai
mesh_terms: D000935:Antifungal Agents / Q000737:chemistry / Q000378:metabolism*; D053898:Biosynthetic Pathways / Q000235:genetics*; D002176:Candida albicans / Q000187:drug effects*; D060847:Metabolic Engineering; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D010866:Natamycin / Q000737:chemistry / Q000378:metabolism*; D013302:Streptomyces / Q000235:genetics* / Q000378:metabolism
chemical_list: D000935:Antifungal Agents; D010866:Natamycin