Resistance-gene directed discovery of bioactive natural products

doi:10.12211/2096-8280.2023-099

Synthetic Biology Journal ›› 2024, Vol. 5 ›› Issue (3): 474-491.DOI: 10.12211/2096-8280.2023-099

• Invited Review • Previous Articles Next Articles

Resistance-gene directed discovery of bioactive natural products

Yongxiang SONG¹^,²^,³, Xiufeng ZHANG¹^,²^,³, Yanqin LI¹^,²^,³, Hua XIAO¹^,²^,³, Yan YAN¹^,²^,³

^1.Key Laboratory of Tropical Marine Bio-resources and Ecology，Guangdong Key Laboratory of Marine Materia Medica，Innovation Academy of South China Sea Ecology and Environmental Engineering，South China Sea Institute of Oceanology，Chinese Academy of Sciences，Guangzhou 510301，Guangdong，China
^2.Sanya Institute of Ocean Eco-Environmental Engineering，Sanya 572000，Hainan，China
^3.University of Chinese Academy of Sciences，Beijing 100049，China

Received:2023-12-01 Revised:2024-03-08 Online:2024-07-12 Published:2024-06-30
Contact: Yan YAN

自抗性基因导向的活性天然产物挖掘

宋永相¹^,²^,³, 张秀凤¹^,²^,³, 李艳芹¹^,²^,³, 肖华¹^,²^,³, 闫岩¹^,²^,³

^1.中国科学院热带海洋生物资源与生态重点实验室，广东省海洋药物重点实验室，中国科学院南海生态环境工程创新研究院，中国科学院南海海洋研究所，广东广州 510301
^2.三亚海洋生态环境工程研究院，海南三亚 572000
^3.中国科学院大学，北京 100049

通讯作者: 闫岩
作者简介:宋永相（1980—），男，博士，副研究员。研究方向为海洋微生物活性物质的发掘与应用。E-mail：songx@scsio.ac.cn
闫岩（1986—），男，博士，研究员。研究方向为海洋活性天然产物的挖掘与合成生物学智造。E-mail：yyan@scsio.ac.cn
基金资助:
国家自然科学基金(32000044);国家重点研发计划(2022YFC2805000);海南省科技计划三亚崖州湾科技城联合项目(2021CXLH0013)

Abstract

Abstract:

Natural products play a crucial role as sources of therapeutic agents for human being and agricultural pesticides. With the development of sequencing technologies, genome mining employing various bioinformatic tools has become an important approach for discovering more natural products. Due to the large number of natural product biosynthetic gene clusters, screening those capable of generating the most potent bioactive molecules has gained significance. To avoid self-destruction, some bioactive molecule producers have evolved with self-resistance enzymes, which are slightly mutated versions of original enzymes, but not sensitive to the bioactive compounds. The presence of self-resistance enzymes in the biosynthetic gene cluster of natural products serves as an indicator for the biosynthesis of bioactive compounds. On the other hand, the biosynthetic gene clusters of natural products could be located using information with their structures and activities as probes, e.g. the accumulating knowledge on antibiotic resistance mechanisms has facilitated the discovery of new antibiotics. Moreover, dereplication of natural products with known resistance mechanisms has been achieved by using indicator strains expressing the resistance genes. While these approaches have successfully utilized self-resistance genes to connect molecules with their biological activities, a more impactful application is to accurately link biological activity with genomic information through target-guided mining of natural products. The concept is to use a self-resistance gene as a predictive tool to screen and identify biosynthetic gene clusters encoding compounds that inhibit specific targets. Recent breakthroughs in self-resistance gene identification have bridged the gap between activity-guided and genome-driven approaches for natural product discovery and functional assignment. This review summarizes progress in bioactive natural product discovery guided by self-resistance genes, as well as its applications, which include the following points: 1) locating biosynthetic gene clusters based on self-resistance genes, 2) predicting the targets of secondary metabolites through self-resistance genes, 3) rapid dereplication of bioactive compounds with self-resistance mechanisms, 4) genome mining of bioactive natural products guided by the target and the internal connection with self-resistance genes, and 5) the development of genome data mining tools directed by self-resistance genes.

Key words: natural products, self-resistance genes, genome mining, biosynthesis, biosynthetic gene clusters

摘要：

天然产物是医药与农药的重要来源。基因组测序和生物信息学分析技术的飞速发展，揭示了大量功能未知的天然产物生物合成基因簇，利用生物信息学工具，从这些庞大的基因簇数据中挖掘活性天然产物已经成为发现新型天然药物的重要途径。天然产物的生产者们利用自抗性基因所表达的自抗性酶来保护自身，这种自抗性酶是体内一些初级代谢途径中管家酶的变体，不但对于活性天然产物具有较好的耐受性，还可以在生产活性天然产物的同时确保宿主体内代谢的正常进行。因而，自抗性基因指导的天然产物研究有效地将活性导向和基因组导向的天然产物发掘策略桥连起来，为精准发掘具有目标活性的新型天然产物提供了有效策略。本文对利用自抗性基因作为探针进行天然产物发掘的代表性研究工作进行了整理和总结，并对研究趋势进行了展望，主要包括：①对于活性已知的天然产物，利用其自抗性基因来定位生物合成基因簇的研究；②以天然产物生物合成基因簇中的自抗性基因为线索，预测产物的作用靶点的研究；③利用天然产物自抗性机制，将具有已知作用机制的活性分子进行快速排重的研究；④利用自抗性基因与天然产物及其活性的内在联系，以目标靶点导向的活性天然产物基因组挖掘；⑤自抗性基因导向的基因组数据挖掘工具的发展情况。

关键词: 天然产物, 自抗性基因, 基因组挖掘, 生物合成, 基因簇

CLC Number:

Q819

Yongxiang SONG, Xiufeng ZHANG, Yanqin LI, Hua XIAO, Yan YAN. Resistance-gene directed discovery of bioactive natural products[J]. Synthetic Biology Journal, 2024, 5(3): 474-491.

宋永相, 张秀凤, 李艳芹, 肖华, 闫岩. 自抗性基因导向的活性天然产物挖掘[J]. 合成生物学, 2024, 5(3): 474-491.

Figures/Tables 8

Fig. 1 Workflow for natural product discovery

Fig. 2 Simultaneous localization of genes encoding core biosynthetic enzymes and for self-resistance(a) Microorganisms produce natural products (black triangles) as a strategy to kill competitors by inhibiting their essential metabolic enzymes (yellow balls). To ensure their own survival, these microorganisms express the self-resistance enzymes (red balls) capable of complementing the functions of those targeted metabolic enzymes; (b) Simultaneous localization of the core enzymes for lovastatin biosynthesis (blue) and the self-resistance genes encoding HMG-CoA reductase within lovastatin biosynthetic gene cluster (BGC). This gene cluster includes another copy of HMGR encoded by lovR (red).

Fig. 3 Self-resistance gene directed localization of the biosynthetic gene clusters (BGCs) for the production of natural products(The biosynthetic core genes, self-resistance genes and other related genes are shown in blue, red and grey, respectively.)

Fig. 4 Determination of the target of natural products through their resistance genes(Biosynthetic core genes, self-resistance genes and other related genes are shown in blue, red and grey, respectively.)

Fig. 5 Workflow of the resistance gene directed dereplication of natural products① Construction of vectors expressing a known antibiotic resistance gene; ② Construction of strains capable of indicating the presence of known bioactive compounds; ③ Construction of a library of indicator strains; ④ Inoculation of the indicator strains to media containing bioactive natural products; ⑤ Identification of natural products with new modes of action; ⑥ Isolation of natural products with new modes of action

Fig. 6 Discovery of bioactive natural products guided by their resistance genes(Biosynthetic core genes, self-resistance genes and other related genes are shown in blue, red and grey, respectively.)

Fig. 7 “False positive” resistance genes in the biosynthetic gene clusters of natural products(Biosynthetic core genes, self-resistance genes and other related genes are shown in blue, red and grey, respectively.)(a) An IMPDH was localized with the biosynthetic genes of pyranonigrin, which exhibit no IMPDH inhibition activity (purple); (b) Albomycin δ2 is an inhibitor of seryl-tRNA synthetase (red), however the seryl-tRNA synthetase homolog is encoded in the BGC with another inhibitor of seryl-tRNA synthetase SB-203208, which functions as a core enzyme (purple) encoded by the biosynthetic gene.

Fig. 8 Discovery of new antibiotics guided by the resistance gene phylogeny(Among 71 BGCs for the biosynthesis of glycopeptides, the self-resistance determinants of complestatin and corbomycin are different from the known determinants vanY and vanHAX in the phylogeny.)

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Resistance-gene directed discovery of bioactive natural products

自抗性基因导向的活性天然产物挖掘

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