微生物药物研究开发现状与思考

doi:10.6040/j.issn.1671-7554.0.2021.0963

摘要/Abstract

摘要： 微生物来源的药物在抗感染、抗肿瘤、免疫抑制和代谢调节等疾病领域发挥着重要作用。抗生素的长期不当使用导致了耐药细菌的产生和蔓延,给公共卫生和安全健康带来了全球性的挑战,寻找新型的抗生素已迫在眉睫。如何从微生物中发掘化学结构和作用机制新颖的新药以对抗愈发严峻的细菌耐药性,已成为当今微生物药物研发面临的新挑战。论文对微生物药物研发历史进行了回顾,并对截至2019年9月在欧美等发达国家上市的微生物药物的数量、产生菌来源和临床适应证进行了归纳总结。最后,针对创新微生物药物研发的迫切性,对微生物药物研发新策略进行了展望。

关键词: 微生物药物, 抗生素, 耐药性, 药物研发策略

Abstract: Microbial drugs play important roles in a panel of therapeutic areas, such as anti-infection, anti-cancer, immunosuppression and metabolic disorder. The long-term abuse of antibiotics has led to the emergence and widespread of drug-resistant bacteria, bringing unprecedented challenges worldwide to the safe and healthy development of public health. Therefore, there is an urgent need for research and development of novel antibiotics. How to discover new drugs with novel chemical structure and mechanism of action from microorganisms to combat the increasingly severe bacterial resistance has become a new challenge for the research and development of microbial drugs. In this review, we gave an overview of the history of microbial drug discovery. The number, producer and indication of the microorganism-derived clinic drugs approved by developed countries, between 1940 and 2019 were also summarized. In addition, due to the urgent need for novel microbial drugs, new strategies for microbiological drug research and development were summarized.

Key words: Microbial drugs, Antibiotics, Drug resistance, Strategies for drug research and development

中图分类号:

R574

鞠建华,杨镇业,李青连,韩亚楠,李艳青,乔伊君,杨虎,张华然. 微生物药物研究开发现状与思考[J]. 山东大学学报 (医学版), 2021, 59(9): 43-50.

JU Jianhua, YANG Zhenye, LI Qinglian, HAN Yanan, LI Yanqing, QIAO Yijun, YANG Hu, ZHANG Huaran. Advances on drugs derived from microbial sources and future perspectives[J]. Journal of Shandong University (Health Sciences), 2021, 59(9): 43-50.

参考文献

[1] Sinh BK, Macdonald CA. Drug discovery from uncultivable microorganisms [J]. Drug Discov Today, 2010, 15(17-18): 792-799.
[2] Seipke RF, Martin K, Hutchings MI. Streptomyces as symbionts: an emerging and widespread theme? [J]. Fems Microbiol Rev, 2012, 36(4): 862-876.
[3] Klassen JL. Microbial secondary metabolites and their impacts on insect symbioses [J]. Curr Opin Insect Sci, 2014, 4: 15-22. doi: 10.1016/j.cois.2014.08.004.
[4] Traxler MF, Kolter R. Natural products in soil microbe interactions and evolution [J]. Nat Prod Rep, 2015, 32(7): 956-970.
[5] Oneill J. Tackling drug-resistant infections globally: final report and recommendations: the review on tntimicrobial tesistance [EB/OL].(2016-05-18)[2021-08-13]. https://wellcomecollection.org/works/thvwsuba.
[6] Shu YZ. Recent natural products based drug development: a pharmaceutical industry perspective [J]. J Nat Prod, 1998, 61(8): 1053-1071.
[7] Hutchings MI, Truman AW, Wilkinson B. Antibiotics: past, present and future [J]. Curr Opin Microbiol, 2019, 51: 72-80. doi: 10.1016/j.mib.2019.10.008.
[8] 张帆. 青霉素的发现简史[J].生物学教学, 2008, 33(7): 70-71.
[9] 王磊, 任东明. 青霉素——从发现到应用[J].生物学通报, 2006, 41(12): 61-62.
[10] Julius H, 刘琼华, 黄世义. 有益的发现——链霉素的故事[J].国外医学(微生物学分册), 1980(1): 47-48.
[11] Bérdy J. Bioactive microbial metabolites [J]. J Antibiot(Tokyo), 2005, 58(1): 1-26.
[12] 寇宏. 细菌耐药性研究进展[J].畜禽业, 2020, 31(3): 37.
[13] Bérdy J. Recent developments of antibiotic research and classification of antibiotics according to chemical structure [J]. Adv Appl Microbiol, 1974, 18(0): 309-406.
[14] Newman DJ, Cragg GM. Natural products as sources of new drugs over the nearly four decades from 01/1981 to 09/2019 [J]. J Nat Prod, 2020, 83(3): 770-803.
[15] Zan J, LI Z, Tianero MD, et al. A microbial factory for defensive kahalalides in a tripartite marine symbiosis [J]. Science, 2019, 364(6445): eaaw6732. doi: 10.1126/science.aaw6732.
[16] Zhang F, Zhao M, Braun DR, et al. A marine microbiome antifungal targets urgent-threat drug-resistant fungi [J]. Science, 2020, 370(6519): 974-978.
[17] Donia MS, Cimermancic P, Schulze CJ, et al. A systematic analysis of biosynthetic gene clusters in the human microbiome reveals a common family of antibiotics [J]. Cell, 2014, 158(6): 1402-1414.
[18] Zipperer A, Konnerth MC, Laux C, et al. Human commensals producing a novel antibiotic impair pathogen colonization [J]. Nature, 2016, 535(7613): 511-516.
[19] Lincke T, Behnken S, Ishida K, et al. Closthioamide: an unprecedented polythioamide antibiotic from the strictly anaerobic bacterium Clostridium cellulolyticum [J]. Angew Chem Int Ed Engl, 2010, 49(11): 2011-2013.
[20] Ling LL, Schneider T, Peoples AJ, et al. A new antibiotic kills pathogens without detectable resistance [J]. Nature, 2015, 517(7535): 455-459.
[21] Nichols D, Cahoon N, Trakhtenberg EM, et al. Use of ichip for high-throughput in situ cultivation of "uncultivable" microbial species [J]. Appl Environ Microbiol, 2010, 76(8): 2445-2450.
[22] Medema MH, de Rond T, Moore BS. Mining genomes to illuminate the specialized chemistry of life [J]. Nat Rev Genet, 2021, 22(9): 553-571.
[23] Liu N, Abramyan ED, Cheng W, et al. Targeted genome mining reveals the biosynthetic gene clusters of natural product cyp51 inhibitors [J]. J Am Chem Soc, 2021, 143(16): 6043-6047.
[24] Yan Y, Liu QK, Zang X, et al. Resistance-gene directed discovery of a natural-product herbicide with a new mode of action [J]. Nature, 2018, 559(7714): 415-418.
[25] Rutledge PJ, Challis GL. Discovery of microbial natural products by activation of silent biosynthetic gene clusters [J]. Nat Rev Microbiol, 2015, 13(8): 509-523.
[26] Yamanaka K, Reynolds KA, Kersten RD, et al. Direct cloning and refactoring of a silent lipopeptide biosynthetic gene cluster yields the antibiotic taromycin A [J]. Proc Natl Acad Sci U S A, 2014, 111(5): 1957-1962.
[27] Wright GD. Opportunities for natural products in 21^st century antibiotic discovery [J]. Nat Prod Rep, 2017, 34(7): 694-701.
[28] Wright GD. Antibiotic adjuvants: rescuing antibiotics from resistance [J]. Trends Microbiol, 2016, 24(11): 862-871.
[29] Perry JA, Koteva K, Verschoor CP, et al. A macrophage-stimulating compound from a screen of microbial natural products [J]. J Antibiot(Tokyo), 2015, 68(1): 40-46.
[30] Garland M, Loscher S, Bogyo M. Chemical strategies to target bacterial virulence [J]. Chem Rev, 2017, 117(5): 4422-4461.
[31] PEW Trust. Antibiotics currently in global clinical development [EB/OL].(2021-03-09)[2021-08-13]. https://www.pewtrusts.org/en/research-and-analysis/data-visualizations/2014/antibiotics-currently-in-clinical-development.

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