Metabolic Blockade-Based Genome Mining of Sea Anemone-Associated Streptomyces sp. S1502 Identifies Atypical Angucyclines WS-5995 A-E: Isolation, Identification, Biosynthetic Investigation, and Bioactivities

Yuyang Wang; Le Zhou; Xiaoting Pan; Zhangjun Liao; Nanshan Qi; Mingfei Sun; Hua Zhang; Jianhua Ju; Junying Ma

doi:10.3390/md22050195

Metabolic Blockade-Based Genome Mining of Sea Anemone-Associated Streptomyces sp. S1502 Identifies Atypical Angucyclines WS-5995 A-E: Isolation, Identification, Biosynthetic Investigation, and Bioactivities

Mar Drugs. 2024 Apr 25;22(5):195. doi: 10.3390/md22050195.

Authors

Yuyang Wang^{1

2}, Le Zhou¹, Xiaoting Pan³, Zhangjun Liao⁴, Nanshan Qi³, Mingfei Sun³, Hua Zhang⁴, Jianhua Ju^{1

2}, Junying Ma^{1

2}

Affiliations

¹ CAS Key Laboratory of Tropical Marine Bio-Resources and Ecology, RNAM Center for Marine Microbiology, Guangdong Key Laboratory of Marine Materia Medica, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Haizhu District, Guangzhou 510301, China.
² College of Oceanology, University of Chinese Academy of Sciences, Qingdao 266400, China.
³ Key Laboratory of Livestock Disease Prevention of Guangdong Province, Key Laboratory of Avian Influenza and Other Major Poultry Diseases Prevention and Control, Ministry of Agriculture and Rural Affairs, Institute of Animal Health, Guangdong Academy of Agricultural Sciences, Guangzhou 510640, China.
⁴ Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Institute of Laboratory Medicine, Guangdong Medical University, Dongguan 523808, China.

Abstract

Marine symbiotic and epiphyte microorganisms are sources of bioactive or structurally novel natural products. Metabolic blockade-based genome mining has been proven to be an effective strategy to accelerate the discovery of natural products from both terrestrial and marine microorganisms. Here, the metabolic blockade-based genome mining strategy was applied to the discovery of other metabolites in a sea anemone-associated Streptomyces sp. S1502. We constructed a mutant Streptomyces sp. S1502/Δstp1 that switched to producing the atypical angucyclines WS-5995 A-E, among which WS-5995 E is a new compound. A biosynthetic gene cluster (wsm) of the angucyclines was identified through gene knock-out and heterologous expression studies. The biosynthetic pathways of WS-5995 A-E were proposed, the roles of some tailoring and regulatory genes were investigated, and the biological activities of WS-5995 A-E were evaluated. WS-5995 A has significant anti-Eimeria tenell activity with an IC₅₀ value of 2.21 μM. The production of antibacterial streptopyrroles and anticoccidial WS-5995 A-E may play a protective role in the mutual relationship between Streptomyces sp. S1502 and its host.

Keywords: Streptomyces sp. S1502; WS-5995; anticoccidial activity; biosynthesis; metabolic blockade-based genome mining.

MeSH terms

Angucyclines and Angucyclinones
Animals
Anthraquinones / pharmacology
Anti-Bacterial Agents / pharmacology
Biological Products / pharmacology
Biosynthetic Pathways / genetics
Genome, Bacterial
Multigene Family*
Sea Anemones*
Streptomyces* / genetics
Streptomyces* / metabolism

Substances

Anti-Bacterial Agents
Biological Products
Anthraquinones
Angucyclines and Angucyclinones

Grants and funding

This research was funded by Fundamental Research & Applied Fundamental Research Major Project of Guangdong Province (2019B030302004), National Natural Science Foundation of China (U23A20107, 82022067, 22037006), Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (2019BT02Y262), Open program of Shenzhen Bay Laboratory (SZBL2021080601006), Rising Star Foundation of the South China Sea Institute of Oceanology (NHXX2019SW0101), and Nansha District Science and Technology Plan Project (NSJL202102).