Halogenase-Targeted Genome Mining Leads to the Discovery of (±) Pestalachlorides A1a, A2a, and Their Atropisomers
Mengna Luo,
Mengyuan Wang,
Shanshan Chang,
Ning He,
Guangzhi Shan,
Yunying Xie
Affiliations
Mengna Luo
CAMS Key Laboratory of Synthetic Biology for Drug Innovation, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Tiantan Xili No.1, Beijing 100050, China
Mengyuan Wang
CAMS Key Laboratory of Synthetic Biology for Drug Innovation, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Tiantan Xili No.1, Beijing 100050, China
Shanshan Chang
CAMS Key Laboratory of Synthetic Biology for Drug Innovation, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Tiantan Xili No.1, Beijing 100050, China
Ning He
CAMS Key Laboratory of Synthetic Biology for Drug Innovation, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Tiantan Xili No.1, Beijing 100050, China
Guangzhi Shan
CAMS Key Laboratory of Synthetic Biology for Drug Innovation, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Tiantan Xili No.1, Beijing 100050, China
Yunying Xie
CAMS Key Laboratory of Synthetic Biology for Drug Innovation, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Tiantan Xili No.1, Beijing 100050, China
Genome mining has become an important tool for discovering new natural products and identifying the cryptic biosynthesis gene clusters. Here, we utilized the flavin-dependent halogenase GedL as the probe in combination with characteristic halogen isotope patterns to mine new halogenated secondary metabolites from our in-house fungal database. As a result, two pairs of atropisomers, pestalachlorides A1a (1a)/A1b (1b) and A2a (2a)/A2b (2b), along with known compounds pestalachloride A (3) and SB87-H (4), were identified from Pestalotiopsis rhododendri LF-19-12. A plausible biosynthetic assembly line for pestalachlorides involving a putative free-standing phenol flavin-dependent halogenase was proposed based on bioinformatics analysis. Pestalachlorides exhibited antibacterial activity against sensitive and drug-resistant S. aureus and E. faecium with MIC values ranging from 4 μg/mL to 32 μg/mL. This study indicates that halogenase-targeted genome mining is an efficient strategy for discovering halogenated compounds and their corresponding halogenases.
