医药微生物技术

吴长生

教授
博士/硕士生导师
个人简介 科研项目 学术论文 其他介绍

2019.07——至今

山东大学微生物国重室

教授

2017.04-2019.06

美国洛克菲勒大学

博士后

宏基因组学

2015.09-2017.02

荷兰莱顿大学

博士后

分子生物技术

2011.09-2015.08

荷兰莱顿大学

博士

放线菌代谢组学

2008.09-2011.06

山东大学

硕士

天然产物化学

2004.09-2008.06

山东大学

本科

药学


研究兴趣

主要从事药源微生物的分离鉴定、活性先导化合物的发现、生物合成及合成生物学结构改造等方面的研究工作,主要包括:

1. 微生物药物发现。采用微生物学手段,从深海沉积物、沙漠、昆虫等不同生态环境中分离次生代谢产物丰富的放线菌和黏细菌,再整合基因组学与代谢组学手段进行高通量筛选微生物资源库,以人工智能机器学习的大数据分析为指导,靶向分离和鉴定具有生物活性的小分子先导化合物前药。此外,利用宏基因组学原理,结合二代、三代基因组测序技术,通过生物信息学指导基因合成和异源表达,挖掘环境中未培养微生物中的天然产物“暗物质”。

2. 复杂微生物次生代谢产物的生物合成研究。用分子生物学手段克隆完整的生物合成基因簇,探索结构新颖、活性独特的微生物次生代谢产物的所涉及的新酶学机制,指导天然药物结构多样化和仿生有机合成。

3. 合成生物学绿色制造。利用代谢工程原理,体内重构如埃博霉素、雷帕霉素等重要医药品的生物合成路径,实现产品在工业生产菌中的改良与产量提升;同时利用组合生物合成的手段创造“非天然”的天然产物,筛选新的生物活性。

1. 科技部,国家重点研发计划“绿色生物制造”重点专项子课题,2021YFC2101002,原料药工业菌种改造关键技术及产业示范,2021.07-2025.06,在研,主持;

2. 山东省自然科学基金,优秀青年项目,ZR2020YQ62, 微生物活性天然产物的发现,2021.01-2023.12,在研,主持;

3. 国家自然科学基金,面上项目,81973215,基因序列标签法高通量挖掘钙离子依赖的酸性脂多肽抗生素,2020.01-2023.12,在研,主持;

4. 国家自然科学基金,青年项目,31900042,基于代谢组学挖掘黄色粘球菌亲缘识别过程中诱导的次生代谢产物,2020.01-2022.12,在研,主持;

5. 科技部,国家重点研发计划“合成生物学” 重点专项子课题,2019YFA09005700,天然产物“暗物质”定向挖掘的平台技术,2020.01-2024.12,在研,主持;

6. 山东大学“齐鲁青年学者”学科建设经费,微生物来源的活性天然产物的发现,2018.08-2023.07,在研,主持。

7. 荷兰科学研究组织(NWO)博士后基金项目(Rubicon grant),019.163LW.018,宏基因组学方法挖掘Diels-Alderase以发现新抗生素,2017.04-2019.03,已结题,主持。

1. Zhang, P.; Zhang, L.; Diao, X. T.; Li, S.; Li, D. D.; Zhang, Z.; Fang, J.; Tang, Y. J.; Wu, D. L.;Wu, C. *; Li, Y. Z.* Docking-guided rational engineering of a macrolide glycosyltransferase to glycodiversify epothilone B.Commun. Biol.2021. Accepted.

2. Wu,C.*, #; Yin, Y. #; Zhu, L. L.; Zhang, Y. M.; Li, Y.-Z.* Metagenomic Sequencing Driven Multidisciplinary Approaches to Shed Light on The Untapped Microbial Natural Products.Drug Discovery Today.2021, 10.1016/j.drudis.2021.11.008.

3. Hu, W. F. #; Niu, L. #; Yue, X. J.; Zhu, L. L.; Hu, W.; Li, Y.-Z.*;Wu,C.* Characterization of Constitutive Promoters forThe Elicitation of Secondary Metabolites in Myxobacteria.ACS Synth. Biol.2021, 10, 2904?2909.

4. Wang, D. G. #; Niu, L. #; Lin, Z. M.; Wang, J. J.; Gao, D. F.; Sui, H. Y.; Li, Y.-Z. *;Wu,C.* The Discovery and Biosynthesis of Nicotinic Myxochelins from anArchangium sp. SDU34.J. Nat. Prod.2021,84, 2744?2748.

5. Li, Y.#; Zhuo L.#; Li, X.; Zhu, Y.; Wu, S.; Shen, T.; Hu, W.; Li, Y.-Z.*;Wu,C.*. Myxadazoles, Myxobacterium-Derived Isoxazole-Benzimidazole Hybrids with Cardiovascular Activities.Angew. Chem. Int. Ed.2021,60, 21679 –21684.

6. Hu, J. Q#; Wang, J. J. #; Li, Y. L.; Zhuo, L.; Zhang, A.; Sui, H. Y.; Li, X. J.; Shen, T.; Wu, Z. H.; Hu, W.; Li, Y. Z.*;Wu,C.* Combining NMR-basedmetabolic profiling andgenome mining for the accelerated discovery of archangiumide, an allenic macrolide from the myxobacteriumArchangium violaceum SDU8.Org. Lett.2021, 23, 2114–2119.

7. Zhang, P.; Zhang, Z.; Zhang, L. J.; Wang, J. J.;Wu,C.*; Glycosyltransferase GT1 family: Phylogenetic distribution, substrates coverage, and representative structural features.Comput. Struct. Biotechnol. J. 2020,18, 1383–1390.

8. Zhang, P.; Zhang, L.; Yue, X. J.; Tang, Y. J.;Wu,C.*; Li, Y. Z.* Effects of glycosylation on the bioactivity of rapamycin.Appl. Microbiol. Biotechnol.2020, 104, 9125-9134.

9. Xiao, X.; Elsayed, S. S.; Wu, C.; van der Heul, H. U.; Metsa-Ketela, M.; Du, C.; Prota, A. E.; Chen, C.C.; Liu, W.; Guo, R.T.; Abrahams, J.P.; van Wezel, G. P. Functional and Structural Insights into a Novel Promiscuous Ketoreductase of the Lugdunomycin Biosynthetic Pathway.ACS Chem. Biol. 2019,15, 2529–2538.

10. Zhang, P.; Zhang, Z.; Li, Z. F.; Chen, Q.; Li, Y. Y.; Gong, Y.; Yue, X. J.; Sheng, D. H.; Zhang, Y. M.;Wu,C.*; Li, Y. Z.* Phylogeny-guided Characterization of Glycosyltransferases for Epothilone Glycosylation.Microbiol. Biotech.2019, 12,763-774.

11. Wu, C.#; ShangZ.#; Lemetre C.; Ternei M. A. ; Brady S. F.; Cadasides, calcium-dependent acidic lipopeptides from the soil metagenome that are active against multidrug resistant bacteria.J. Am. Chem. Soc.2019, 141, 3910-3919.

12. Machushynets N.;Wu, C. *; Elsayed S. S.; Hankemeier T.; van Wezel G. P. * Discovery of novel glycerolated quinazolinones fromStreptomyces sp. MBT27.J. Ind. Microbiol. Biotechnol. 2019.46, 483-492.

13. Wu, C.; van der Heul, H.U.; Melnik, A. V.; Luebben, J.; Pannu, N.; Dorrestein, P. C.; Choi, Y. H.; van Wezel, G. P. Lugdunomycin, an angucycline-derived molecule with unprecedented chemical architecture.Angew. Chem. Int. Ed.2019,58,2809 –2814.

14. Gubbens, J.; Wu, C.;Zhu, H.;Filippov,D. V.;Florea, B. L.;Rigali, S.;Overkleeft, H. S.; van Wezel, G. P. Intertwined Precursor Supply during Biosynthesis of the Catecholate–Hydroxamate Siderophores Qinichelins in Streptomyces sp. MBT76.ACS Chem. Biol. 2017,12, 2756–2766.

15. Wu, C.; Du, C.; Ichinose, K.;Choi, Y. H.; van Wezel, G. P. Discovery ofC-glycosylpyranonaphthoquinones inStreptomyces sp. MBT76 by a combined NMR-based metabolomics and bioinformatics workflow. J. Nat. Prod. 2017, 80, 269–277.

16. Wu, C.; Ichinose, K.;Choi, Y. H.; van Wezel, G. P. Aromatic Polyketide GTRI-02 is a previously unidentified product of the act gene cluster inStreptomyces coelicolor A3(2).ChemBioChem.2017, 18, 1428–1434.

17. Wu, C.; Medema, M. H.; L?kamp, R. M.; Zhang, L.; Dorrestein, P. C.; Choi, Y. H.; van Wezel, G. P. Leucanicidin and Endophenasides Result from Methyl-Rhamnosylation by the Same Tailoring Enzymes inKitasatospora sp. MBT66.ACS Chem. Biol. 2016,11, 478–490.

18. Wu, C.#; Zhu, H.#; van Wezel, G. P.; Choi, Y. H. Metabolomics-guided analysis of isocoumarin production by Streptomyces species MBT76 and biotransformation of flavonoids and phenylpropanoids.Metabolomics 2016, 12:90.

19. Wu, C.; Choi, Y. H.; van Wezel, G. P. Metabolic profiling as a tool for prioritizing antimicrobial compounds.J. Ind. Microbiol. Biotechnol.2016,43, 299–312.

20. Wu, C.; Du, C.; Gubbens, J.; Choi, Y. H.; van Wezel, G. P. Metabolomics-Driven Discovery of a Prenylated Isatin Antibiotic Produced byStreptomyces Species MBT28.J. Nat. Prod.2015,78, 2355–2363.

21. Wu, C.; Kim, H. K.; van Wezel, G. P.; Choi, Y. H. Metabolomics in the natural products field – a gateway to novel antibiotics.Drug Discov. Today Technol.2015,13, 11–17.

22. Wu, C.; Zacchetti, B.; Ram, A. F. J.; van Wezel, G. P.; Claessen, D.; Choi, Y. H. Expanding the chemical space for natural products byAspergillus-Streptomyces co-cultivation and biotransformation.Sci. Rep.2015,5, 10868.

23. Wu, C.; van Wezel, G. P.; Choi, Y. H. Identification of novel endophenaside antibiotics produced byKitasatospora sp. MBT66.J. Antibiot. (Tokyo).2015,68, 445–452.

24. Wu, C.; Lin, Z.; Wang, L.; Guo, D. Phenolic Compounds with NF-κB Inhibitory Effects from the FungusPhellinus baumii.Bioorg. Med. Chem. Lett. 2011,21, 3261–3267.

所获奖励

1.2015年莱顿大学优秀博士毕业奖

2. 2017年莱顿大学科学学院c.j.kok jury award


专利

1. 吴长生,李岳兰,李越中;一组美沙达唑类化合物及其制备方法和应用;中国发明专利申请

2. 李越中,吴长生,李岳兰,吴姝鸽,王晶晶,一株产美沙达唑类化合物的黏细菌及其应用;中国发明专利申请

3. 李越中,张鹏,吴长生,汤亚杰,埃博霉素B的氮乙酰葡萄糖苷或半乳糖苷化合物及其酶法制备与应用;中国发明专利申请

4. 李越中,张鹏,吴长生,汤亚杰,一组埃博霉素B葡萄糖苷类化合物及其酶法制备与应用;中国发明专利申请

5. 李越中,张鹏,张礼娟,吴长生,汤亚杰,一组雷帕霉素葡萄糖苷类化合物及其酶法制备与应用;中国发明专利申请

6. Wu, C.; Choi, Y. H.; van Wezel, G. P. Methods of preparation and use of novel polyketides. European PatentApplication.WO 2016195495