Identification and Proposed Relative and Absolute Configurations of Niphimycins C-E from the Marine-Derived Streptomyces sp. IMB7-145 by Genomic Analysis.

Abstract

Analysis of the whole genome sequence of Streptomyces sp. IMB7-145 revealed the presence of seven type I polyketide synthase biosynthetic gene clusters, one of which was highly homologous to the biosynthetic gene cluster of azalomycin F. Detailed bioinformatic analysis of the modular organization of the PKS gene suggested that this gene is responsible for niphimycin biosynthesis. Guided by genomic analysis, a large-scale cultivation ultimately led to the discovery and characterization of four new niphimycin congeners, namely, niphimycins C-E (1-3) and 17-O-methylniphimycin (4). The configurations of most stereocenters of niphimycins have not been determined to date. In the present study, the relative configurations were elucidated by spectroscopic analysis, including J-based analysis and the CNMR database method. Further, the full absolute configurations of niphimycins were completely proposed for the first time based on biosynthetic gene cluster analysis of the ketoreductase and enoylreductase domains for hydroxy- and methyl-bearing stereocenters. Compounds 1, 3, 4, and niphimycin Iα (5) showed antimicrobial activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci (MIC: 8-64 μg/mL), as well as cytotoxicity against the human HeLa cancer cell line (IC50: 3.0-9.0 μM). In addition, compounds 1 and 5 displayed significant activity against several Mycobacterium tuberculosis clinical isolates (MIC: 4-32 μg/mL).

• Authors: Yuanyuan Hu, Mian Wang, Chunyan Wu, Yi Tan, Jiao Li, Xiaomeng Hao, Yanbo Duan, Yan Guan, Xiaoya Shang, Yiguang Wang, Chunling Xiao, Maoluo Gan
• Journal: Journal of natural products (J Nat Prod) Vol. 81 Issue 1 Pg. 178-187 (01 26 2018) ISSN: 1520-6025 [Electronic] United States
• PMID: 29308897 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Bacterial Agents
• Guanidines
• Macrolides
• azalomycin-F
• niphimycin
• Polyketide Synthases

Topics

• Anti-Bacterial Agents (chemistry, pharmacology)
• Aquatic Organisms (chemistry)
• Cell Line, Tumor
• Genomics (methods)
• Guanidines (chemistry, pharmacology)
• HeLa Cells
• Hep G2 Cells
• Humans
• K562 Cells
• MCF-7 Cells
• Macrolides (chemistry)
• Methicillin-Resistant Staphylococcus aureus (drug effects)
• Multigene Family (genetics)
• Polyketide Synthases (genetics)
• Streptomyces (chemistry, genetics)