Research Progress on Metabolites of Marine Streptomyces Under the Strategy of Activating Silencing Genes

doi:10.19586/j.2095-2341.2024.0141

Current Biotechnology ›› 2025, Vol. 15 ›› Issue (1): 19-26.DOI: 10.19586/j.2095-2341.2024.0141

• Reviews • Previous Articles Next Articles

Research Progress on Metabolites of Marine Streptomyces Under the Strategy of Activating Silencing Genes

Boxuan WANG(), Jiaxin CHEN, Jiajun CAI, Kunxian LI, Jiachun LIN, Lingzhi TANG, Xuan HONG()

Xiamen Key Laboratory of Marine Medicinal Natural Products Resources，Xiamen Medical College，Fujian Xiamen 361023，China

Received:2024-08-28 Accepted:2024-10-14 Online:2025-01-25 Published:2025-03-07
Contact: Xuan HONG

海洋链霉菌隐性次级代谢产物基因簇激活的研究进展

王博轩(), 陈佳鑫, 蔡佳君, 李昆贤, 林家纯, 唐灵芝, 洪璇()

厦门医学院，厦门市海洋药用天然产物资源重点实验室，福建厦门 361023

通讯作者: 洪璇
作者简介:王博轩 E-mail：1246884719@qq.com；
基金资助:
福建省大学生创新创业训练项目(202412631010);厦门市自然科学基金面上项目(3502Z20227227);厦门医学院校级科研项目(K2023-25);厦门医学院教育教学改革研究项目(XBKS2022002)

Abstract

Abstract:

Marine Streptomyces are the source of the valuable lead compounds with medicinal biological activity due to their complex morphological differentiation cycle， which often accompanied by complex physiological changes. But most of the biosynthetic gene clusters of secondary metabolites in marine Streptomyces are “silent”. The article reviewed the methods for predicting the expression potential of “silent genes” and summarized the means of activating “silent genes”， including changing culture conditions， chemically inducing gene cluster expression and biological mediation， in order to provide new avenues for the mining of secondary metabolites in marine Streptomyces.

Key words: marine Streptomyces, silent genes, multi efficiency method

摘要：

海洋链霉菌具有复杂的发育分化周期，在进行形态分化的同时常伴随着复杂的生理变化，因此，海洋链霉菌是具有生物活性的先导化合物的重要来源。然而，海洋链霉菌次级代谢产物的大部分生物合成基因簇是沉默状态。综述了预测“沉默基因”表达潜力的方法，总结了激活“沉默基因”表达的手段，包括改变培养条件、化学诱导基因簇表达和生物介导等，以期为海洋链霉菌次级代谢产物的挖掘提供新的途径。

关键词: 海洋链霉菌, 沉默基因, 多效性方法

CLC Number:

S917.1

Boxuan WANG, Jiaxin CHEN, Jiajun CAI, Kunxian LI, Jiachun LIN, Lingzhi TANG, Xuan HONG. Research Progress on Metabolites of Marine Streptomyces Under the Strategy of Activating Silencing Genes[J]. Current Biotechnology, 2025, 15(1): 19-26.

王博轩, 陈佳鑫, 蔡佳君, 李昆贤, 林家纯, 唐灵芝, 洪璇. 海洋链霉菌隐性次级代谢产物基因簇激活的研究进展[J]. 生物技术进展, 2025, 15(1): 19-26.

Figures/Tables 2

References 47

1	VAN DER MEIJ A, WORSLEY S F, HUTCHINGS M I, et al.. Chemical ecology of antibiotic production by actinomycetes[J]. FEMS Microbiol. Rev., 2017, 3: 392-416.
2	宋国栋, 廖宏娟, 张志斌, 等. 非定向激活沉默基因簇挖掘链霉菌活性次级代谢产物研究进展[J]. 天然产物研究与开发, 2023, 35(8):1442-1456.
	SONG G D, LIAO H J, ZHANG Z B, et al.. Advances in non-directed activation of silent gene clusters for mining active secondary metabolites of Streptomyces [J]. Nat.Prod.Res.Dev., 2023, 35(8): 1442-1456.
3	XUE Z, WANG S, SUN J, et al.. Research progress on morphological differentiation and secondary metabolite biosynthesis of Streptomyces [J]. Acta Microbiol. Sin., 2021, 61(12): 3870-3886.
4	WANG C, MEI X, ZHU W. A brief introduction to natural products derived from marinestreptomyces[J]. Mar. Sci. J., 2016, 10: 86-124.
5	陈巧莉, 黄杰, 陈森瑜, 等. 海洋链霉菌次级代谢产物研究进展[J]. 生物技术进展, 2023, 13(06): 844-852.
	CHEN Q L, HUANG J, CHEN S Y, et al.. Research progress on secondary metabolites of marine streptomyces[J]. Curr. Biotechnol., 2023, 13(6): 844-852.
6	许爽. 基于共培养探索黑曲霉L14和镰刀菌R1次级代谢产物研究[D]. 浙江: 浙江工业大学, 2023.
7	刘象博. 土壤微生物及海洋链霉菌次级代谢产物生物合成基因的挖掘[D]. 江苏: 南京农业大学, 2018.
8	WANG R. Marine streptomyces research on metabolites and their antibacterial activity[J]. Chin. J. Marine Drugs, 2023, 42(1): 20-24.
9	SCHORN M A, ALANJARY M M, AGUINALDO K, et al.. Sequencing rare marine actinomycete genomes reveals high density of unique natural product biosynthetic gene clusters[J]. Microbiology, 2016, 162(12): 2075-2086.
10	刘象博, 柴树茂, 曹明明, 等. 海洋链霉菌Streptomyces sp.MCCC 1A09830抗菌成分的分离与鉴定[J]. 食品工业科技, 2020, 41(9): 108-113+118.
	LIU X B, CHAI S M, CAO M M, et al.. Isolation and identification of antimicrobial active substance produced by marine Streptomyces sp. MCCC 1A09830[J]. Sci. Technol. Food Industr., 2020, 41(9): 108-113+118.
11	KALKREUTER E, PAN G, CEPEDA A J, et al.. Targeting bacterial genomes for natural product discovery[J]. Trends Pharmacol. Sci., 2020, 41(1): 13-26.
12	LEWIS K. The science of antibiotic discovery[J]. Cell, 2020, 181(1): 29-45.
13	KAUTSAR S A, BLIN K, SHAW S, et al.. MIBiG 2.0: a repository for biosynthetic gene clusters of known function[J]. Nucleic Acids Res., 2020, 48(D1): 454-458.
14	YANG Z J, HE J, WEI X, et al..Exploration and genome mining of natural products from marine Streptomyces [J]. Appl. Microbiol.Biotechnol., 2019,104(1):67-76.
15	LI S. Research on metabolites of marine derived Streptomyces IMB18-531 and Cladosporium IMB19-099 co-cultured[J]. Acta Pharmaceutica Sin., 2023, 58(4): 967-974.
16	HU Z, WENG Q, CAI Z, et al.. Optimization of fermentation conditions and medium components for chrysomycin a production by Streptomyces sp. 891-B6[J]. BMC Microbiol., 2024, 24(1): 120[2024-12-30]. .
17	张永贺. 深海链霉Streptomyces somaliensis SCSIO ZH66中隐性次级代谢产物合成基因簇的激活及其产物发酵优化[D]. 青岛: 中国海洋大学, 2015.
18	UNDABARRENA A, UGALDE J A, SEEGER M, et al.. Genomic data mining of the marine actinobacteria Streptomyces sp. H-KF8 unveils insights into multi-stress related genes and metabolic pathways involved in antimicrobial synthesis[J/OL]. PeerJ, 2017, 5: e2912[2024-12-30]. .
19	RATEB M E, HALLYBURTON I, HOUSSEN W E, et al.. Induction of diverse secondary metabolites in Aspergillus fumigatus by microbial co-culture[J]. RSC Adv., 2013, 3(34):14444-14450.
20	ZHANG X, WANG X, HUANG T, et al.. Ammosamide natural products from sponge-derived Streptomyces sp. S52-B[J]. Microbiol. China, 2021, 48(7): 2298-2306.
21	ZHANG C, DING W, QIN X. et al.. Genome sequencing of Streptomyces olivaceus SCSIO T05 and activated production of lobophorin CR4 via metabolic engineering and genome mining[J/OL]. Mar. Drugs, 2019, 17(10): 593[2024-12-30]. .
22	DING W, TU J, ZHANG H, et al.. Genome mining and metabolic profiling uncover polycyclic tetramate macrolactams from Streptomyces koyangensis SCSIO 5802[J/OL]. Mar. Drugs, 2021, 19(8): 440[2024-12-30]. .
23	ALMEIDA E L, KAUR N, JENNINGS L K, et al.. Genome mining coupled with OSMAC-based cultivation reveal differential production of surugamide A by the marine sponge isolate Streptomyces sp. SM17 when compared to its terrestrial relative S. albidoflavus J1074[J/OL]. Microorganisms, 2019, 7(10): 394[2024-12-30]. .
24	BAE M, AN J S, BAE E S, et al.. Donghaesulfins a and B, dimeric Benz[a]anthracene thioethers from volcanic island derived Streptomyces sp.[J]. Org. Lett., 2019, 21(10): 3635-3639.
25	KIM T S, SHIN Y H, LEE H M, et al.. Ohmyungsamycins promote antimicrobial responses through autophagy activation via AMP-activated protein kinase pathway[J/OL]. Sci. Rep., 2017, 7: 3431[2024-12-30]. .
26	BAE M, AN J S, HONG S H, et al.. Donghaecyclinones A-C:new cytotoxic rearranged angucyclinones from a volcanic island-derived marine Streptomyces sp.[J/OL]. Mar. Drugs, 2020, 18(2):E121[2024-12-30]. .
27	BODE H B, BETHE B, HÖFS R, et al.. Big effects from small changes:possible ways to explore nature's chemical diversity[J]. Chembiochem, 2002, 3(7): 619-627.
28	SCHWARZ J, HUBMANN G, ROSENTHAL K, et al.. Triaging of culture conditions for enhanced secondary metabolite diversity from different bacteria[J/OL]. Biomolecules, 2021, 11(2): 193[2024-12-30]. .
29	王冉. 多种生境来源放线菌次级代谢产物的初步研究[D]. 南宁: 广西大学, 2016.
30	何昊. pH-营养联合调控促进北极海洋链霉菌生产二活菌素[D]. 华东理工大学, 2016.
31	PHAM V T T, NGUYEN H T, NGUYEN C T, et al.. Identification and enhancing production of a novel macrolide compound in engineered Streptomyces peucetius [J]. RSC Adv., 2021, 11(5):3168-3173.
32	PAN R, BAI X, CHEN J, et al.. Exploring structural diversity of microbe secondary metabolites using OSMAC strategy: a literature review[J/OL]. Front. Microbiol., 2019, 10: 294[2024-12-30]. .
33	项仁鑫, 杨小虎, 方佳双, 等. 响应面法优化链霉菌HY6-S36产星孢菌素的发酵条件[J]. 中国抗生素杂志, 2021, 46(8):749-755.
	XIANG R X, YANG X H, FANG J S, et al.. Optimization fermentation conditions of staursporine from Streptomyces sp. HY6-S36 by response surface methodology[J]. Chin. J. Antibiot., 2021, 46(8): 749-755.
34	ZHOU H, JIANG Y, XU Y X, et al.. Research on quorum sensing inhibitory activity and culture condition of a marine Streptomyces parvulus [J]. Biotechnol. Bull., 2019, 35(10): 137-143.
35	HORINOUCHI S, BEPPU T. A-factor as a microbial hormone that controls cellular differentiation and secondary metabolism in Streptomyces griseus [J]. Mol. Microbiol., 1994, 12(6): 859-864.
36	KICHOUH-AIADI S, GALLARDO-RODRÍGUEZ J J, CERÓN-GARCÍA M C, et al.. Exploring the potential of epigenetic chemicals to increase metabolite production in the dinoflagellate microalga Amphidinium carterae [J]. J. Appl. Phycol., 2024, 36(3): 1169-1179.
37	袁慧敏, 李伟, 郑永标, 等. 链霉菌沉默基因簇激活的多效性方法研究进展[J]. 药物生物技术, 2022, 29(1): 72-76.
	YUAN H M, LI W, ZHENG Y B, et al.. Advances in pleiotropic mthods for activation of slent gene custers in Streptomyces[J]. Chin. J. Pharm. Biotechnol., 2022, 29(1): 72-76.
38	ZHANG M M, WONG F T, WANG Y J, et al.. CRISPR-Cas9 strategy for activation of silent Streptomyces biosynthetic gene clusters[J]. Nat. Chem. Biol., 2017, 13: 607-609.
39	TOMM H A, UCCIFERRI L, ROSS A C. Advances in microbial culturing conditions to activate silent biosynthetic gene clusters for novel metabolite production[J]. J.Ind.Microbiol.Biotechnol., 2019, 46(9): 1381-1400.
40	崔阳阳. PPTase过表达激活链霉菌沉默生物合成基因簇的研究[D]. 南京农业大学, 2022.
41	YUSHCHUK O, OSTASH I, MÖSKER E, et al.. Eliciting the silent lucensomycin biosynthetic pathway in Streptomyces cyanogenus S136 via manipulation of the global regulatory gene adpA[J/OL]. Sci. Rep., 2021, 11: 3507[2024-12-30]. .
42	QIAN Z Y, BRUHN T, PAUL M . et al .. Discovery of the streptoketides by direct cloning and rapid heterologous expression of a cryptic PKS II gene cluster from Streptomyces sp. Tü6314[J]. J. Org. Chem., 2020, 85(2):664-673.
43	BRAKHAGE A A, SCHROECKH V. Fungal secondary metabolites-strategies to activate silent gene clusters[J]. Fungal Genet. Biol., 2011, 48(1): 15-22.
44	SUN L, ZENG J, CUI P, et al.. Manipulation of two regulatory genes for efficient production of chromomycins in Streptomyces reseiscleroticus [J]. J. Biol. Eng., 2018, 12: 9[2024-12-30]. .
45	KITANI S, HOSHIKA M, NIHIRA T. Disruption of sscR encoding a γ-butyrolactone autoregulator receptor in Streptomyces scabies NBRC 12914 affects production of secondary metabolites[J]. Folia Microbiol., 2008, 53(2): 115-124.
46	HUO L, HU G J, FU C. Heterologous expression of bacterial natual product biosynthetic pathways[J]. Nat. Prod. Rep., 2019, 36: 1412-1436.
47	XU M, ZHANG F, CHENG Z, et al.. Functional genome mining reveals a class V lanthipeptide containing a d-amino acid introduced by an F₄₂₀ H₂-dependent reductase[J]. Angew Chem. Int. Ed. Engl., 2020, 59(41): 18029-18035.

来源	方法	化合物	生物活性	参考文献
Streptomyces sp. IMB18-531	共培养（Cladosporium sp. IMB19-099）	铝草氨菌素E、去铁胺E、铁草氨菌素E、Terragine E、卡巴西霉素、环 (L-脯氨酰-L-酪氨酸)、邻氨基苯甲酸、(Z)-14-甲基十五烷-9-烯酸和(Z)-十六烷-8-烯酸	去铁胺E显示出抗肝纤维化活性;卡巴西霉素、(Z)-14-甲基十五烷-9-烯酸和(Z)-十六烷-8-烯酸对甲氧西林耐药金葡菌、表皮葡萄球菌、枯草芽孢杆菌显出抗菌活性	[15]
Streptomyces sp. 891-B6	改变培养条件	金黄毒素A	用于治疗革兰氏阳性细菌感染和癌症	[16]
Streptomycessomaliensis SCSIO ZH66	核糖体工程	弗德利卡毒素	具有抗癌活性	[17]
Streptomyces sp. H-KF8	改变培养条件	诺卡胺素、麦角甾醇、星形孢菌素	诺卡胺素具有抑制病原菌的活性，麦角甾醇对多株肿瘤细胞株具有抑制毒性，星形孢菌素具有非常有效的蛋白激酶抑制活性	[18]
Streptomyces bullii	共培养( Aspergillus fumigatus MBC-F1-10)	Brevianamide、螺旋前列腺素 A、6-methoxy spirotryprostain B、烟曲霉震颤素B、烟曲霉震颤C、12，13-dihydroxy deriva tive、疣孢青霉原	均有灭杀寄生虫的活性	[19]
Streptomyces sp. S52-B	OSMAC策略	Ammosamide A、Ammosamide B、Ammosalic acid	化合物Ammosamide A和Ammosamide B具有优良的抗癌活性	[20]
Streptomyces sp. SCSIO T05	代谢工程	Lobophorin CR4	具有抗菌活性	[21]
Streptomyces koyangensis SCSIO 5802	基因组挖掘	10-epi-HSAF、Koyanamide A	10-epi-HSAF能够抑制多种卵菌和真菌活性	[22]
Streptomyces sp. SM17	基因组挖掘	Surugamide A	具有抗癌和抗真菌活性	[23]
Streptomyces sp. SUD119	化学诱导	Donghaecyclinones A-C	具有抗菌、抗真菌和抗癌活性	[24-26]

来源	方法	化合物	生物活性	参考文献
Streptomyces sp. IMB18-531	共培养（Cladosporium sp. IMB19-099）	铝草氨菌素E、去铁胺E、铁草氨菌素E、Terragine E、卡巴西霉素、环 (L-脯氨酰-L-酪氨酸)、邻氨基苯甲酸、(Z)-14-甲基十五烷-9-烯酸和(Z)-十六烷-8-烯酸	去铁胺E显示出抗肝纤维化活性;卡巴西霉素、(Z)-14-甲基十五烷-9-烯酸和(Z)-十六烷-8-烯酸对甲氧西林耐药金葡菌、表皮葡萄球菌、枯草芽孢杆菌显出抗菌活性	[15]
Streptomyces sp. 891-B6	改变培养条件	金黄毒素A	用于治疗革兰氏阳性细菌感染和癌症	[16]
Streptomycessomaliensis SCSIO ZH66	核糖体工程	弗德利卡毒素	具有抗癌活性	[17]
Streptomyces sp. H-KF8	改变培养条件	诺卡胺素、麦角甾醇、星形孢菌素	诺卡胺素具有抑制病原菌的活性，麦角甾醇对多株肿瘤细胞株具有抑制毒性，星形孢菌素具有非常有效的蛋白激酶抑制活性	[18]
Streptomyces bullii	共培养( Aspergillus fumigatus MBC-F1-10)	Brevianamide、螺旋前列腺素 A、6-methoxy spirotryprostain B、烟曲霉震颤素B、烟曲霉震颤C、12，13-dihydroxy deriva tive、疣孢青霉原	均有灭杀寄生虫的活性	[19]
Streptomyces sp. S52-B	OSMAC策略	Ammosamide A、Ammosamide B、Ammosalic acid	化合物Ammosamide A和Ammosamide B具有优良的抗癌活性	[20]
Streptomyces sp. SCSIO T05	代谢工程	Lobophorin CR4	具有抗菌活性	[21]
Streptomyces koyangensis SCSIO 5802	基因组挖掘	10-epi-HSAF、Koyanamide A	10-epi-HSAF能够抑制多种卵菌和真菌活性	[22]
Streptomyces sp. SM17	基因组挖掘	Surugamide A	具有抗癌和抗真菌活性	[23]
Streptomyces sp. SUD119	化学诱导	Donghaecyclinones A-C	具有抗菌、抗真菌和抗癌活性	[24-26]

Research Progress on Metabolites of Marine Streptomyces Under the Strategy of Activating Silencing Genes

海洋链霉菌隐性次级代谢产物基因簇激活的研究进展

RichHTML

PDF

Knowledge

Abstract

Cite this article

share this article

Figures/Tables 2

References 47

Related Articles 1

Recommended Articles

Metrics

Comments