Characterization of Tailoring Steps of Nargenicin A1 Biosynthesis Reveals a Novel Analogue with Anticancer Activities

• Published in: ACS chemical biology Vol. 15; no. 6; pp. 1370 - 1380
• Main Authors: Dhakal, Dipesh, Han, Jang Mi, Mishra, Ravindra, Pandey, Ramesh Prasad, Kim, Tae-Su, Rayamajhi, Vijay, Jung, Hye Jin, Yamaguchi, Tokutaro, Sohng, Jae Kyung
• Format: Journal Article
• Language: English
• Published: United States 19.06.2020
• Subjects: Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - metabolism; Anti-Bacterial Agents - pharmacology; Antineoplastic Agents - chemistry; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Biosynthetic Pathways; Cell Cycle - drug effects; Cell Line, Tumor; Genes, Bacterial; Humans; Lactones - chemistry; Lactones - metabolism; Lactones - pharmacology; Multigene Family; Neoplasms - drug therapy; Nocardia - genetics; Nocardia - metabolism; Streptomyces - genetics; Streptomyces - metabolism
• ISSN: 1554-8929; 1554-8937
• DOI: 10.1021/acschembio.9b01034

Nargenicin A1( ) is an antibacterial macrolide with effective activity against various Gram-positive bacteria, including methicillin-resistant . Due to the promising properties of this compound in inhibiting cell proliferation, immunomodulation, and the cell protective effect, there has been significant interest in this molecule. Recently, the biosynthetic gene cluster (BGC) of was reported from and . In addition, two crucial enzymes involved in the formation of the core decalin moiety and postmodification of the decalin moiety by an ether bridge were characterized. This study reports on the BGC of from sp. CS682. In addition, the direct capture and heterologous expression of BGC from sp. CS682 in led to the production of . Further metabolic profiling of wild type, sp. CS682 in optimized media (DD media) resulted in the isolation of two acetylated derivatives, 18- -acetyl-nodusmicin and 18- -acetyl-nargenicin. The post-PKS modification pathway in biosynthesis of was also deciphered by identifying intermediates and/or enzymatic reactions of NgnP1, NgnM, and NgnO3. Different novel analogues of , such as compound , compound , 23-demethyl 8,13-deoxy-nodusmicin ( ), 23-demethyl 8,13-deoxynargenicin ( ), 8,13-deoxynodusmicin ( ), and 8,13-deoxynargenicin ( ), were also characterized, which extended our understanding of key post-PKS modification steps during the biosynthesis of . In addition, the antimicrobial and anticancer activities of selected analogues were also evaluated, whereas compound was shown to exhibit potent antitumor activity by induction of G2/M cell cycle arrest, apoptosis, and autophagy.