基于复杂天然产物的半合成抗生素工艺化学研究进展★

doi:10.6023/cjoc202506002

摘要/Abstract

发现新的抗生素药物是应对细菌和真菌耐药性问题的关键手段, 而基于现有抗生素开发新型抗生素已被证明是一条有效途径. 目前, 临床上或临床试验阶段的抗生素大多是半合成药物, 即通过对天然抗生素进行修饰来解决毒性或耐药性等问题. 天然抗生素产物的复杂性和稳定性使得半合成抗生素的药物化学开发面临较高难度, 而其后续的合成工艺则更具挑战. 这类工艺化学不仅需要解决化学、区域和立体选择性的转化难题, 还需克服分离纯化等技术障碍. 在抗生素发展的百年历程中, 化学家们已经发展了许多经典的抗生素化学合成工艺, 如四环素化学和大环内酯化学等. 重点介绍了这些经典的抗生素半合成工艺, 从化学合成挑战、原研工艺与改进工艺以及可能的工艺优化等方面进行详细阐述.

关键词: 抗生素, 半合成, 工艺化学, 发酵, 抗细菌药物, 抗真菌药物

Discovering new antibiotic drugs is a critical approach to addressing the issue of bacterial and fungal resistance. Developing novel antibiotic based on existing ones has proven to be an effective strategy. Currently, due to issues such as resistance and toxicity, many antibiotics have been developed into semi-synthetic drugs that are either on the market or in clinical trials. The complexity and stability of natural antibiotic products make the pharmaceutical chemistry development of semi-synthetic antibiotics particularly challenging, with subsequent synthetic processes presenting even greater difficulties. These process chemistries must address challenges in chemical, regio-, and stereo-selective transformations, as well as overcome technical obstacles in separation and purification. Over the century-long history of antibiotic development, chemists have developed many classic antibiotic chemical synthesis processes, such as tetracycline chemistry and macrolide chemistry. These classic semi-synthetic antibiotic processes are reviewed, detailing the chemical synthesis challenges, original and improved processes, and potential process optimizations.

Key words: antibiotic, semi-synthesis, process chemistry, fermentation, antibacterial drug, antifungal drug

引用此文

王化南, 吴贺, 赵烨, 顾轶, 陈刚. 基于复杂天然产物的半合成抗生素工艺化学研究进展^★[J]. 有机化学, 2025, 45(9): 3045-3074.

Hua-Nan Wang, He Wu, Ye Zhao, Yi Gu, Gang Chen. Advances in the Process Chemistry of Semisynthetic Antibiotics Based on Complex Natural Products^★[J]. Chinese Journal of Organic Chemistry, 2025, 45(9): 3045-3074.

导出引用 EndNote|Reference Manager|ProCite|BibTeX|RefWorks

分享此文

图/表 25

	Classes of antibiotics	Natural (fermentation)	Semisynthetic
Antibacterial drugs	Penicillins	Penicillin G	via semisynthesis from 6-APA
	Cephalosporins	Cephalosporin C etc.	via semisynthesis from 7-ADCA, 7-ACA, D-7ACA
	Carbapenems		totally synthesized via 4-AA
	Tetracyclines	Oxytetracycline, Tetracycline, Chlorotracycline	Doxycycline, Minocycline, Tigecycline, Omadacycline, Sareycline, Eravacycline (totally synthetic)
	Macrolides	Erythromycin, Tylosin	Clarithromycin, Azithromycin, Dirithromycin, Roxithromycin, Telithromycin, Tilmicosin, Tildipirosin, Tulathromycin
	Aminoglycosides	Streptomycin, Gentamicin, Apramycin, Neomycin	Plazomicin, Etimicin, Amikacin, Arbekacin
	Glycopeptides	Vancomycin, Teicoplanin	Telavancin, Oritavancin, Dalbavancin
	Lincosamides	Lincomycin	Clindamycin, Clindamycin Phosphate, Clindamycin Palmitate, Pirlimycin
	Pleuromutilin	Pleuromutilin	Tiamulin, Valnemulin, Retapamulin, Lefamulin
	Polymyxins	Polymyxin B, Colistin	Colistimethate Sodium, SPR206 (clinical trial), MRX-8 (clinical trial), QPX9003 (clinical trial, total trial)
	Other drugs such as quinolones (total synthesis)
	Rifamycins		Rifampin, Rifapentine, Rifabutin, Rifaximin
Antifungal drugs	Azoles (totally synthetic)
	Amphotericins	Amphotericin B	Am-2-19 (clinical trial)
	Echinocandins		Caspofungin, Micafungin, Anidulafungin, Rezafungin
	Triterpenes		Ibrexafungerp
	Other drugs

表1. 抗菌、抗真菌药物分类

Table 1. Classes of antibacterial and antifungal drugs

图1. 四环素类抗生素

Figure 1. Tetracycline antibiotics

图式1. 四环素半合成工艺

Scheme 1. Process for preparation of semi-synthetic Tetracyclines

图式2. 大环内酯(酮内酯)类抗生素

Scheme 2. Macrolide (ketolide) antibiotics

图式3. 第二代大环内酯类抗生素克拉霉素的合成工艺

Scheme 3. Process for preparation of 2nd macrolide antibiotics Clarithromycin

图式4. 第三代大环内酯类抗生素的合成工艺

Scheme 4. Process for preparation of 3rd macrolide antibiotics

图式5. 半合成大环内酯兽药合成工艺

Scheme 5. Process for preparation of semi-synthetic Veterinary macrolides

图2. 氨基糖苷类抗生素

Figure 2. Aminoglycoside antibiotics

图式6. 普拉佐米星的合成工艺

Scheme 6. Process for preparation of plazomicin

图式7. 地贝卡星、阿贝卡星的合成工艺

Scheme 7. Process for preparation of Dibekacin/Arbekacin

图3. 万古霉素类抗生素

Figure 3. Vancomycin analog antibiotics

图式8. 特拉万星的合成工艺

Scheme 8. Process for preparation of Telavancin

图式9. 达巴万星的合成工艺

Scheme 9. Process for preparation of Dalbavancin

图式10. 奥利万星的合成工艺

Scheme 10. Process for preparation of Oritavancin

图式11. 林可酰胺类抗生素及其合成工艺

Scheme 11. Lincosamide antibiotics and their process for preparation

图4. 利福霉素类抗生素

Figure 4. Rifamycin antibiotics

图式12. 利福平和利福喷丁的合成工艺

Scheme 12. Process for preparation of Rifampicin and Rifapentine

图式13. 利福布汀和利福昔明的合成工艺

Scheme 13. Process for preparation of Rifabutin and Rifabutin

图5. 棘白菌素类抗生素

Figure 5. Echinocandin antibiotics

图式14. 卡泊芬净的合成工艺

Scheme 14. Process for preparation of Caspofungin

图式15. 阿尼芬净和瑞扎芬净的合成工艺

Scheme 15. Process for preparation of Anidulafungin and Rezafungin

图式16. 截短侧耳素类抗生素及其合成工艺

Scheme 16. Pleuromutilin antibiotics and their process for preparation

图式17. 三萜类抗生素及其合成工艺

Scheme 17. Triterpenoid antibiotics and their process for preparation

图6. 多黏菌素类抗G-细菌药物进展

Figure 6. Advances in polymyxin-type anti-gram-negative bacterial drugs

图7. 多烯类抗真菌药物最新进展

Figure 7. Advances in polyene-type antifungal drugs

参考文献 61

[61]	(c) Apgar, J. M.; Wilkening, R. R.; Parker, D. L.; Meng, D.; Wildonger, K. J.; Sperbeck, D.; Greenlee, M. L.; Balkovec, J. M.; Flattery, A. M.; Abruzzo, G. K.; Galgoci, A. M.; Giacobbe, R. A.; Gill, C. J.; Hsu, M.-J.; Liberator, P.; Misura, A. S.; Motyl, M.; Nielsen Kahn, J.; Powles, M.; Racine, F.; Dragovic, J.; Fan, W.; Kirwan, R.; Lee, S.; Liu, H.; Mamai, A.; Nelson, K.; Peel, M. Bioorg. Med. Chem. Lett. 2021, 32, 127661.
[62]	(a) McInturff, E. L.; France, S. P.; Leverett, C. A.; Flick, A. C.; Lindsey, E. A.; Berritt, S.; Carney, D. W.; DeForest, J. C.; Ding, H. X.; Fink, S. J.; Gibson, T. S.; Gray, K.; Hubbell, A. K.; Johnson, A. M.; Liu, Y.; Mahapatra, S.; McAlpine, I. J.; Watson, R. B.; O'Donnell, C. J. J. Med. Chem. 2023, 66, 10150. doi: 10.1021/acs.jmedchem.3c00501 pmid: 37528515
	(b) Greenlee, M. L.; Wilkening, R.; Apgar, J.; Wildonger, K. J.; Meng, D.; Parker, D. L. WO 201001920, 2010. pmid: 37528515
[63]	Hu, X.; Yang, P.; Chai, C.; Liu, J.; Sun, H.; Wu, Y.; Zhang, M.; Zhang, M.; Liu, X.; Yu, H. Nature 2023, 616, 190.
[1]	Walsh, C.; Wencewicz, T. Antibiotics: Challenges, Mechanisms, Opportunities, ASM Press, Washington, DC, 2016.
[2]	Walesch, S.; Birkelbach, J.; Jézéquel, G.; Haeckl, F. P. J.; Hege- mann, J. D.; Hesterkamp, T.; Hirsch, A. K. H.; Hammann, P.; Müller, R. EMBO Rep. 2023, 24, e562033.
[3]	(a) Süssmuth, R. D.; Kulike-Koczula, M.; Gao, P.; Kosol, S. Angew. Chem., Int. Ed. 2025, 64, e202414325.
	(b) Miethke, M.; Pieroni, M.; Weber, T.; Brönstrup, M.; Hammann, P.; Halby, L.; Arimondo, P. B.; Glaser, P.; Aigle, B.; Bode, H. B.; Moreira, R.; Li, Y.; Luzhetskyy, A.; Medema, M. H.; Pernodet, J.-L.; Stadler, M.; Tormo, J. R.; Genilloud, O.; Truman, A. W.; Weissman, K. J.; Takano, E.; Sabatini, S.; Stegmann, E.; Brötz- Oesterhelt, H.; Wohlleben, W.; Seemann, M.; Empting, M.; Hirsch, A. K. H.; Loretz, B.; Lehr, C.-M.; Titz, A.; Herrmann, J.; Jaeger, T.; Alt, S.; Hesterkamp, T.; Winterhalter, M.; Schiefer, A.; Pfarr, K.; Hoerauf, A.; Graz, H.; Graz, M.; Lindvall, M.; Ramurthy, S.; Karlén, A.; van Dongen, M.; Petkovic, H.; Keller, A.; Peyrane, F.; Donadio, S.; Fraisse, L.; Piddock, L. J. V.; Gilbert, I. H.; Moser, H. E.; Müller, R. Nat. Rev. Chem. 2021, 5, 726.
	(c) Hobson, C.; Chan, A. N.; Wright, G. D. Chem. Rev. 2021, 121, 3464.
[4]	(a) Nicolaou, K. C.; Rigol, S. J. Antibiot. 2018, 71, 153. pmid: 28953368
	(b) Rossiter, S. E.; Fletcher, M. H.; Wuest, W. M. Chem. Rev. 2017, 117, 12415. doi: 10.1021/acs.chemrev.7b00283 pmid: 28953368
[5]	(a) Testero, S. A.; Llarrull, L.; Fisher, J. F.; Mobashery, S. In Burger's Medicinal Chemistry, Drug Discovery and Development, 8th ed.; Ed.: Abraham, D. J., Wiley, New York, 2021, Vol. 7, pp 1-188.
	(b) Fisher, J. F.; Mobashery, S. In Privileged Scaffolds in Medicinal Chemistry: Design, Synthesis, Evaluation, RSC Drug Discovery Series No. 50, Royal Society of Chemistry, 2015, pp. 64-97.
[6]	(a) Hlavka, J. J.; Boothe, J. H. Handbook of Experimental Pharmacology: the Tetracyclines, Springer-Verlag KG Berlin, Germany, 1985.
[7]	(a) Blackwood, R. K.; Beereboom, J. J.; Rennhard, H. H.; von Wittenau, M. S.; Stephens, C. R. J. Am. Chem. Soc. 1963, 85, 3943.
	(b) Blackwood, R. K.; Rennhard, H. H.; Beereboom, J. J.; Stephens, C. R.; Blackwood, R. K. US 3200149, 1965.
[8]	Xu, G.-Q.; Gao, Y.; Wu, D.-C.; Mao, L.-F.; Dong, W.-P.; Zhang, Y.-G.; Jiang, Y.-Q.; Li, W. Chem. Res. Appl. 2018, 30, 1708 (in Chinese).
	(徐桂清, 高原, 吴斗灿, 毛龙飞, 董文佩, 张银贵, 姜玉钦, 李伟, 化学研究与应用, 2018, 30, 1708.)
[9]	Xu, G. Q.; Zhu, R. R.; Mao, X. Y.; Mao, L. F.; Wu, D. C.; Gao, Y.; Jiang, Y. Q.; Li, W. Chin. J. Synth. Chem. 2019, 27, 145 (in Chinese).
	(徐桂清, 朱荣荣, 毛雪莹, 毛龙飞, 吴斗灿, 高原, 姜玉钦, 李伟, 合成化学, 2019, 27, 145.)
[10]	(a) Church, R. F. R.; Schaub, R. E.; Weiss, M. J. J. Org. Chem. 1971, 36, 723. pmid: 5545572
	(b) Saito, Y.; Kasai, M.EP 0294762, 1988. pmid: 5545572
[11]	(a) Kiri, N. R.; Patel, S. N.; Akhaja, T.; Sompura, V. B.; Ghumara, R.; Vagdoda, D. R. WO 2022029796, 2022.
	(b) Zhou, R.CN 103044280, 2013.
[12]	(a) Honeyman, L.; Ismail, M.; Nelson, M. L. Antimicrob. Agents Chemother. 2015, 59, 7044. doi: 10.1128/AAC.01536-15 pmid: 26349824
	(b) Chung, J. Y. L.; Hartner, F. W.; Cvetovich, R. J. Tetrahedron Lett. 2008, 49, 6095. pmid: 26349824
[13]	Palombi, G.; Castelli, E.; Motta, G.; Meinrad, B.; Lu, R. L.; Huang, S. Z.; William, A.; Joshi, G.; Faye, S.; Sean, J.WO 2019192614, 2019.
[14]	(a) Charest, M. G.; Lerner, C. D.; Brubaker, J. D. Science 2005, 308, 395. pmid: 15941256
	(b) Charest, M. G.; Siegel, D. R.; Myers, A. G. J. Am. Chem. Soc. 2005, 127, 8292. pmid: 15941256
	(c) Liu, F.; Wright, P. M.; Myers, A. G. Org. Lett. 2017, 19, 206. pmid: 15941256
	(d) Ronn, M.; Zhu, Z.; Hogan, P. C.; Zhang, W.-Y.; Niu, J.; Katz, C. E.; Dunwoody, N.; Gilicky, O.; Deng, Y.; Hunt, D. K.; He, M.; Chen, C.-L.; Sun, C.; Clark, R. B.; Xiao, X.-Y. Org. Process Res. Dev. 2013, 17, 838. pmid: 15941256
	(e) Sun, C.; Hunt, D. K.; Clark, R. B.; Lofland, D.; O’Brien, W. J.; Plamondon, L.; Xiao, X.-Y. J. Med. Chem. 2011, 54, 3704. pmid: 15941256
[64]	Slingerland, C. J.; Martin, N. I. ACS Infect. Dis. 2024, 10, 1056. doi: 10.1021/acsinfecdis.3c00630 pmid: 38470446
[65]	(a) Endo, M. M.; Cioffi, A. G.; Burke, M. D. Synlett 2016, 27, 337.
	(b) Maji, A.; Soutar, C. P.; Zhang, J.; Lewandowska, A.; Uno, B. E.; Yan, S.; Shelke, Y.; Murhade, G.; Nimerovsky, E.; Borcik, C. G.; Arango, A. S.; Lange, J. D.; Marin-Toledo, J. P.; Lyu, Y.; Bailey, K. L.; Roady, P. J.; Holler, J. T.; Khandelwal, A.; SantaMaria, A. M.; Sanchez, H.; Juvvadi, P. R.; Johns, G.; Hageman, M. J.; Krise, J.; Gebremariam, T.; Youssef, E. G.; Bartizal, K.; Marr, K. A.; Steinbach, W. J.; Ibrahim, A. S.; Patterson, T. F.; Wiederhold, N. P.; Andes, D. R.; Pogorelov, T. V.; Schwieters, C. D.; Fan, T. M.; Rienstra, C. M.; Burke, M. D. Nature 2023, 623, 1079.
	(c) Deng, Q.; Li, Y.; He, W.; Chen, T.; Liu, N.; Ma, L.; Qiu, Z.; Shang, Z.; Wang, Z. Nature 2025, 640, 743.
[15]	(a) Abouelhassan, Y.; Garrison, A. T.; Yang, H.; Chav́ez-Riveros, A.; Burch, G. M.; Huigens, R. W. J. Med. Chem. 2019, 62, 7618. doi: 10.1021/acs.jmedchem.9b00370 pmid: 24268476
	(b) Fernandes, P.; Pereira, D.; Watkins, P. B.; Bertrand, D. J. Med. Chem. 2020, 63, 6462. pmid: 24268476
	(c) Villarino, N.; Brown, S. A.; Martín-Jiménez, T. Vet. J. 2013, 198, 352. doi: 10.1016/j.tvjl.2013.07.032 pmid: 24268476
	(d) Zou, X.; Zeng, W.; Chen, C. F.; Qi, X. C.; Qian, J. C.; Chu, J.; Zhuang, Y. P.; Zhang, S, L.; Li, W. J. Biotechnol. Bioprocess Eng. 2010, 15, 959. pmid: 24268476
[16]	(a) Morimoto, S.; Takahashi, T.; Watanabe, Y.; Omura, S. J. Antibiot. 1984, 37, 187. pmid: 6706855
	(b) Watanabe, Y.; Morimoto, S.; Goi, M.; Mitsukuchi, M.; Adachi, T.; Nakagami, J.; Asaka, T.; Eguchi, T.; Sota, K.EP 0158467, 1985. pmid: 6706855
	(c) Suh, K.-H.; Seong, M.-R.; Kim, N.-D.; Lee, G.-S. US 6809188, 2004. pmid: 6706855
	(d) Xu, Q.; Liu, Y.; Zhang, G.; Zhu, L.; Lu, J.; Lyu, J.; Lyu, M.; Wu, J.; Kong, L.CN 116574143, 2023. pmid: 6706855
[17]	Ran, X.; Huang, X.; Hao, D.; Wang, C.; Meng, L.; Zhu, L.; Lyu, M.; Wang, L.; Liang, W.; Xu, S.; Cheng, Y.CN 117417388, 2024.
[18]	(a) Yan, J.; Jiang, W.; Hu, M.CN 106188187, 2016.
	(b) McGill, J. M. EP 0535900A1, 1993.
[19]	Yan, F.; Ma, Z.-Q. Hebei Chem. Ind. 2006, 29, 6 (in Chinese).
	(闫峰, 马忠青, 河北化工, 2006, 29, 6.)
[20]	(a) Lu, L. J.; Wei, F.; Tang, Y. Y.; Luo, S. Z.; Lin, X. Q.; Yang, Y. R. CN 101235063, 2008.
	(b) Deshpande, P. B.; Patel, M. K.; Dhameliya, K. H.; Luthra, P. K. US 2008051352, 2008.
	(c) Richardson, P. F.; Campos, K. R.; Butcher, J. W.; Grabowski, E. J. J. Org. Process Res. Dev. 2006, 10, 446.
[21]	Zhong, Z.; Du, C.; Luo, Z.; Song, S.; Liao, G.; Yao, J.; Goldmann, S.; Wang, Z. Org. Process Res. Dev. 2017, 21, 1371.
[22]	(a) Fang, M.; Ning, S.; Liu, Q.; Kong, M.; Wu, L.CN 102382159, 2012.
	(b) Wang, Y.; Zhou, L.; Wang, B.CN 103483406, 2014.
	(c) Fang, M.; Liu, Q.; Kong, Q.; Kong, M.; Wu, L.; Tian, Z.CN 106905397, 2017.
	(d) Kong, X.; Wang, X.; Zhang, Y.CN 104725451, 2015.
[23]	(a) Zhang, W.; Sun, K.; Fu, Y.; Peng, K.; Zhang, Z.; Jiang, Y.CN 112679570, 2021.
	(b) Blatter, F.; Brenner, M.; Brink, M.; Fleischhauer, K.; Hu, G.; Niedermann, H. P.; Rager, T.; Schweisel, T.; Veit, S.; Warrass, R.; Wennesheimer, G. J. WO 2008012343, 2008.
	(c) Du, T.; Gu, C.; Sun, B.; Lv, Z.; Gao, J.; Chen, Y.; Hao, F.; Sun, R.CN 103880903, 2014.
	(d) Fang, M.; Li, Y.; Liu, Q.; Kong, M.; Wu, L.CN 102863487, 2012.
[24]	(a) Yuan, J.; Fu, X.; Cong, Q.; Yu, H.; Xu, T.CN 107501364, 2017.
	(b) Yin, M.; Wu, D.; Wen, W.CN 108473524, 2018.
	(c) Xu, J.; Kou, J.; Wang, Z.; Liao, G.; Chen, Y.; Luo, Z.; Huang, F.CN 110903335, 2020.
[25]	(a) Seiple, I. B.; Zhang, Z.; Jakubec, P.; Langlois-Mercier, A.; Wright, P. M.; Hog, D. T.; Yabu, K.; Allu, S. R.; Fukuzaki, T.; Carlsen, P. N.; Kitamura, Y.; Zhou, X.; Condakes, M. L.; Szczypiński, F. T.; Green, W. D.; Myers, A. G. Nature 2016, 533, 338.
	(b) Myers, A. G.; Clark, R. B. Acc. Chem. Res. 2021, 54, 1635.
[26]	(a) Böttger, E. C.; Crich, D. ACS Infect. Dis. 2020, 6, 168. doi: 10.1021/acsinfecdis.9b00441 pmid: 29296992
	(b) Mingeot-Leclercq, M. P.; Glupczynski, Y.; Tulkens, P. M. Antimicrob. Agents Chemother. 1999, 43, 727. doi: 10.1128/AAC.43.4.727 pmid: 29296992
	(c) Chandrika, N. T.; Garneau-Tsodikova, S. Chem. Soc. Rev. 2018, 47, 1189. doi: 10.1039/c7cs00407a pmid: 29296992
	(d) Fan, J., Zhao, M. Chin. J. Antibiot. 2019, 44, 1229 (in Chinese). pmid: 29296992
	(范瑾, 赵敏, 中国抗生素杂志, 2019, 44, 1229 ) pmid: 29296992
[27]	(a) Aggen, J.; Goldblum, A. A.; Linsell, M.; Dozzo, P.; Moser, H. E.; Hildebrandt, D.; Gliedt, M.WO 2009067692, 2009.
	(b) Li, Z.; Zhao, H.; Zhu, X.; Peng, K.; Li, Z.; Li, H.; Liu, Y.; Yang, Q.; Zheng, C.CN 110878108, 2020.
	(c) Zhu, X.; Zhao, H.; Li, Z.; Peng, K.; Fan, S.; Yang, Q.; Mu, Y.; Cong, Z.; Li, H.; Zheng, C.CN 110885350, 2020.
[28]	(a) Wei, Z.; Li, J.; Zhi, L.CN 102093444, 2011.
	(b) Chou-Hong, T.; Thiruvengadam, T. K.; Chiu, J. S.; Colon, C.; Green, M. D. US 5442047, 1995.
	(c) Wang, H.; Han, C.CN 101469007, 2009.
	(d) Chen, Y. C. CN 1259328C, 2006.
[29]	(a) Zhang, Y.; Lin, M.; Tang, S.CN 118290499, 2024.
	(b) Chou-Hong, T.; Thiruvengadam, T. K.; Chiu, J. S.-H.; Colon, C.EP 0219093, 1987.
	(c) Nam, G.; Kim, S. H.; Kim, J.-H.; Shin, J.-H.; Jang, E.-S. Org. Process Res. Dev. 2002, 6, 78.
	(d) Qiang, G.; Wang, J.CN 106866756, 2017.
	(e) Ge, X.-B.; Yang, J.-F.; Sun, Y.-G.; Wang, Y.-H.; Zhang, W.-H.; Li, X.-K.; Wang, Y.-S.; Zhang, J.; Ma, J.-F. CN 103833804, 2014.
[30]	(a) Wang, S.; Zhang, K.; Cai, C.; Chu, J.; Sun, Z.; Bu, B.; Sun, X.; Wang, F.CN 106866755, 2017.
	(b) Cai, C.; Chu, J.; Sun, Z.; Wang, S.; Gu, Z.; Li, B.; Wu, K.; Fan, C.; Zhang, Z.; Dong, T.CN 104356182, 2015.
[31]	(a) Umezawa, H.; Umezawa, S.; Seki, S.; Fukatsu, S.; Yasuda, S.US 4357465, 1982.
	(b) Qiao, R.; Cai, Y.; Sun, Z.; Wu, K.; Fan, C.; Zhang, J.; Zhang, P.CN 102786564, 2012.
	(c) Qiao, R. Z.; Zhang, J.; Zhou, H.; Li, C.; Cai, Y.; Guo, L.WO 2014166139, 2014.
	(d) Li, J.; Qiao, R.; Zhang, H.; Liu, K.; Li, C.CN 115716856, 2023.
	(e) Qiao, R.; Zhang, J.; Zhou, H.; He, H.; Zhang, Y.; Wang, Y.CN 103204887, 2013.
[32]	(a) Quirke, J. C. K.; Rajasekaran, P.; Sarpe, V. A.; Sonousi, A.; Osinnii, I.; Gysin, M.; Haldimann, K.; Fang, Q.-J.; Shcherbakov, D.; Hobbie, S. N.; Sha, S.-H.; Schacht, J.; Vasella, A.; Böttger, E. C.; Crich, D. J. Am. Chem. Soc. 2020, 142, 530. pmid: 26024064
	(b) Matsushita, T.; Sati, G. C.; Kondasinghe, N.; Pirrone, M. G.; Kato, T.; Waduge, P.; Kumar, H. S.; Sanchon, A. C.; Dobosz- Bartoszek, M.; Shcherbakov, D.; Juhas, M.; Hobbie, S. N.; Schrepfer, T.; Chow, C. S.; Polikanov, Y. S.; Schacht, J.; Vasella, A.; Böttger, E. C.; Crich, D. J. Am. Chem. Soc. 2019, 141, 5051. doi: 10.1021/jacs.9b01693 pmid: 26024064
	(c) Mandhapati, A. R.; Yang, G.; Kato, T.; Shcherbakov, D.; Hobbie, S. N.; Vasella, A.; Böttger, E. C.; Crich, D. J. Am. Chem. Soc. 2017, 139, 14611. doi: 10.1021/jacs.7b07754 pmid: 26024064
	(d) Matsushita, T.; Chen, W.; Juskeviciene, R.; Teo, Y.; Shcherbakov, D.; Vasella, A.; Böttger, E. C.; Crich, D. J. Am. Chem. Soc. 2015, 137, 7706. doi: 10.1021/jacs.5b02248 pmid: 26024064
	(e) Lubriks, D.; Zogota, R.; Sarpe, V. A.; Matsushita, T.; Sati, G. C.; Haldimann, K.; Gysin, M.; Böttger, E. C.; Vasella, A.; Suna, E.; Hobbie, S. N.; Crich, D. ACS Infect. Dis. 2021, 7, 2413. pmid: 26024064
[33]	(a) Groesen, E. V.; Innocenti, P.; Martin, N. I. ACS Infect. Dis. 2022, 8, 1381. pmid: 15303493
	(b) Barna, J. C.; Williams, D. H. Annu. Rev. Microbiol. 1984, 38, 339. pmid: 15303493
	(c) Westwell, M. S.; Bardsley, B.; Dancer, R. J.; Try, A. C.; Williams, D. H. Chem. Commun. 1996, 589. pmid: 15303493
	(d) Parenti, F.; Beretta, G.; Berti, M.; Arioli, V. J. Antibiot. 1978, 31, 276. pmid: 15303493
	(e) Stogios, P. J.; Savchenko, A. M. Protein Sci. 2020, 29, 654. doi: 10.1002/pro.3819 pmid: 15303493
	(f) Leadbetter, M. R.; Adams, S. M.; Bazzini, B.; Fatheree, P. R.; Karr, D. E.; Krause, K. M.; Lam, B. M. T.; Linsell, M. S.; Nodwell, M. B.; Pace, J. L.; Quast, K.; Shaw, J.; Soriano, E.; Trapp, S. G.; Villena, J. D.; Wu, T. X.; Christensen, B. G.; Judice, J. K. J. Antibiot. 2004, 57, 326. pmid: 15303493
	(g) Mendes, R. E.; Farrell, D. J.; Sader, H. S.; Jones, R. N. Clin. Infect. Dis. 2012, 54, S203. pmid: 15303493
	(h) Leuthner, K. D.; Yuen, A.; Mao, Y.; Rahbar, A. Expert Rev Anti Infect Ther. 2015, 13, 149. pmid: 15303493
[34]	(a) Leadbetter, M. R.; Linsell, M. S.; Lee, J.; Liu, J.US 2003069391, 2003.
	(b) Ma, S.; Jia, J.; Yuan, H.; Cao, S. Chin. J. New Drugs 2013, 22, 2809 (in Chinese).
	(马帅, 贾景雨, 袁红, 曹胜华, 中国新药杂志, 2013, 22, 2809.)
	(c) Liu, L.; Pan, M.; Zhou, J.; Yang, J. Chin. J. Org. Chem. 2015, 35, 2437 (in Chinese).
	(刘泺, 潘敏, 周静珊, 杨金纬, 有机化学, 2015, 35, 2437.) doi: 10.6023/cjoc201505029
	(d) Huang, L. X.; Li, B. B.; Jiang, Q.; Chen, G.; Li, C. B. CN 108948156, 2018.
	(e) Colombo, L.; Malabarba, A.; Stogniew, M.WO 2004045637, 2004.
	(f) Leadbetter, M. R.; Linsell, M. S. WO 2001098328, 2001.
[35]	(a) Gao, H.; Chen, X.; Chen, L.; Zhou, L.; Guan, Y.; Wang, W.CN 116355056, 2023.
[36]	(a) Cooper, R. D. G.; Huff, B. E.; Nicas, T. I.; Quatroc-he, J. T.; Rodriguez, M. J.; Snyder, N. J.; Staszak, M. A.; Thompson, R. C.; Wilkie, S. C.; Zweifel, M. J. EP 0667353, 1995.
	(b) Li, B.; Jiang, Q.; Wang, B.; Chen, Y.; Xie, W.CN 109053864, 2018.
[37]	Wu, Z. C.; Boger, D. L. Acc. Chem. Res. 2020, 53, 2587.
[38]	(a) Mason, D. J.; Dietz, A.; De Boer, C. Antimicrob. Agents Chemother. 1962, 554. pmid: 1929280
	(b) Birkenmeyer, R. D.; Kagan, F. J. Med. Chem. 1970, 13, 616. pmid: 1929280
	(c) Phillips, I. J. Antimicrob. Chemother. 1981, 7 (Suppl. A), 11. pmid: 1929280
	(d) Lai, C. J.; Weisblum, B. Proc. Natl. Acad. Sci. U. S. A. 1971, 68, 856. pmid: 1929280
	(e) Griffith, L. J.; Ostrander, W. E.; Mullins, C. G.; Beswick, D. E. Science 1965, 147, 746. pmid: 1929280
	(f) Leclercq, R.; Courvalin, P. Antimicrob. Agents Chemother. 1991, 35, 1267. doi: 10.1128/AAC.35.7.1267 pmid: 1929280
[39]	(a) Fan, Y.-L.; Liu, X.-G.; Cao, Y.-F.; Zhang, Z.-S.; Ren, Q.-H.; Cao, L.-L.; An, J.-F.; Feng, Y.-H.; Zhao, Z.; Liu, J.-F.; Zhang, N.; Wu, Y.-J. CN 116178462, 2023.
	(b) Zou, J.-Z.; Tang, J.-T.; Yang, X.-Z.; Chen, L.-J.; Wang, C.-X. CN 119569800, 2025.
[40]	Fan, Y.-L.; Cao, Y.-F.; Cang, W.-S.; Cheng, Y.-L.; Yu, Y.-Y.; An, J.-F.; Gong, Y.-R.; Wu, G.-L.; Zhang, Y.-S.; Chen, J.-C.; Zhang, C.-H.; Xue, J.; Wang, X.-J.; Liu, X.-W. CN 110066301, 2019.
[41]	Wei, J.; Liu, Y.CN 202011611072, 2020.
[42]	(a) Ding, C.-Y.; Bremer, N. M.; Smith, T. D.; Seitz, P. K.; Anastasio, N. C.; Cunningham, K. A.; Zhou, J. ACS Chem. Neurosci. 2012, 3, 538.
	(b) Birkenmeyer, R. D. US 4278789, 1981.
	(c) Argoudelis, A. D. US 3284439, 1966.
	(d) Birkenmeyer, R. D. US 3475407, 1969.
	(e) Tao, J. G. M.S. Thesis, Zhejiang University, Hangzhou, 2012 (in Chinese).
	(陶国建, 硕士论文, 浙江大学, 杭州, 2012.)
[43]	(a) Mitcheltree, M. J.; Pisipati, A.; Syroegin, E. A.; Silvestre, K. J.; Klepacki, D.; Mason, J. D.; Terwilliger, D. W.; Testolin, G.; Pote, A. R.; Wu, K. J. Y.; Ladley, R. P.; Chatman, K.; Mankin, A. S.; Polikanov, Y. S.; Myers, A. G. Nature 2021, 599, 507.
	(b) Mitcheltree, M. J.; Pisipati, A.; Syroegin, E. A.; Silvestre, K. J.; Klepacki, D.; Mason, J. D.; Terwilliger, D. W.; Testolin, G.; Pote, A. R.; Wu, K. J. Y.; Ladley, R. P.; Chatman, K.; Mankin, A. S.; Polikanov, Y. S.; Myers, A. G. Nat. Chem. 2025, 17, 582.
[44]	(a) Sensi, P. Rev. Infect. Dis. 1983, 3, 402. pmid: 11290327
	(b) Campbell, E. A.; Korzheva, N.; Mustaev, A.; Murakami, K.; Nair, S.; Goldfarb, A.; Darst, S. A. Cell 2001, 104, 901. doi: 10.1016/s0092-8674(01)00286-0 pmid: 11290327
	(c) Floss, H. G.; Yu, T.-W. J. Am. Chem. Soc. 2005, 105, 621. pmid: 11290327
	(d) Goel, B.; Tripathi, N.; Bhardwaj, N.; Singh, I. P.; Jain, S. K. ChemSelect 2024, 9, e202400554. pmid: 11290327
	(e) Sensi, P.; Margalith, P.; Timhal, M. T. Farmaco, Ed. Sci. 1959, 14, 146147. pmid: 11290327
[45]	(a) Xue, S. L.; Xue, L.; Du, M. S.; Huang, J.; Du, X. Q.; Song, L. X. CN 100383143, 2008.
	(b) Wu, Y. Y.; Chen, K.; Ma, Z. H.; Li, R. Z.; Wu, B.; Ji, L. J.; Zhi, J. W. CN 111848639, 2020.
	(c) Zhu, M.; Ruijter, E.; Wessjohann, L. A. Org. Lett. 2004, 6, 3921.
[46]	(a) Arioli, V.; Berti, M.; Carniti, G.; Randisi, E.; Rossi, E.; Scotti, R. J. Antibiot. 1981, 34, 1026. pmid: 7319918
	(b) Doe, I. S.; Smith, J.; Roe, P. Drugs 1998, 56, 607. pmid: 7319918
[47]	(a) Rossetti, V.; Marsili, L.; Pasqualucci, C.US 4217277, 1980. pmid: 6418702
	(b) Marsili, L.; Franceschi, G.; Ballabio, M.; Oronzo, G.; Vigevani, A.; Ungheri, D. J. Antibiot. 1983, 36, 1495. pmid: 6418702
	(c) Marsili, L.; Rossetti, V.; Pasqualucci, C.GB 1603127, 1981. pmid: 6418702
	(d) Wang, D. X.; Wang, Y.; Yang, J.; Chen, J.; Luo, J.; Li, P.CN 113583021, 2021. pmid: 6418702
[48]	(a) Marchi, E.; Montecchi, L.; Venturini, A. P.; Mascellani, G.; Brufani, M.; Cellai, L. J. Med. Chem. 1985, 28, 960. pmid: 4009619
	(b) Liu, C. X.; Bai, Z. Q., Wang, T. B.; Li, X. Y.; Li, H.CN 101585843, 2009. pmid: 4009619
[49]	(a) Szymański, M.; Chmielewska, S.; Czyżewska, U.; Malinowska, M.; Tylicki, A. J. Enzyme Inhib. Med. Chem. 2022, 37, 876. pmid: 7650681
	(b) Bouffard, F. A.; Zambias, R. A.; Dropinski, J. F.; Balkovec, J. M.; Hammond, M. L.; Abruzzo, G. K.; Bartizal, K. F.; Marrinan, J. A.; Kurtz, M. B.; McFadden, D. C.; Nollstadt, K. H.; Powles, M. A.; Schmatz, D. M. J. Med. Chem. 1994, 37, 222. pmid: 7650681
	(c) Hashimoto, S. J. Antibiot. 2009, 62, 27. doi: 10.1038/ja.2008.3 pmid: 7650681
	(d) Torre, P. D.; Reboli, A. C. Expert Rev. Anti Infect. Ther. 2007, 5, 45. pmid: 7650681
	(b) France, S. P.; Lindsey, E. A.; McInturff, E. L.; Berritt, S.; DeForest, J.; Flick, A. C.; Fink, S.; Gibson, T. S.; Gray, K.; Hubbell, A. K.; Johnson, A. M.; Lie, Y.; Mahapatra, S.; Watson, R. B.; Zhou, Z. J. Med. Chem. 2025, 68, 2147. doi: 10.1021/acs.jmedchem.4c02079 pmid: 7650681
	(c) Debono, M.; Turner, W. W.; LaGrandeur, L.; Burkhardt, F. J.; Nissen, J. S.; Nichols, K. K.; Rodriguez, M. J.; Zweifel, M. J.; Zeckner, D. J.; Gordee, R. S.; Tang, J.; Parr, T. R. Jr. J. Med. Chem. 1995, 38, 3271. pmid: 7650681
[50]	(a) Balkovec, J. M.; Bouffard, F. A.; Black, R. M. WO 9421677, 1994.
	(b) Leonard, W. R.; Belyk, K. M.; Conlon, D. A.; Bender, D. R.; DiMichele, L. M.; Liu, J.; Hughes, D. L. J. Org. Chem. 2007, 72, 2335.
	(c) Leonard, W.; Belyk, K. M. WO 9747645, 1997.
	(d) Belyk, K. M.; Leonard, W. R. Jr. WO 02083713, 2002.
	(e) Hua, B.; Linyu, P.; Pengcheng, Q.; Huan, W.; Kai, Y.; Xufeng, Y.; Fuli, Z. CN 101792486, 2010.
[51]	(a) Ueda, S.; Tanaka, M.; Ezaki, M.; Sakamoto, K.; Hashimoto, S.; Oohata, N.; Tsuboi, M.; Yamashita, M.WO 9732975, 1997. pmid: 18424132
	(b) Tomishima, M.; Ohki, H.; Yamada, A.; Maki, K.; Ikeda, F. Bioorg. Med. Chem. Lett. 2008, 18, 2886. doi: 10.1016/j.bmcl.2008.03.093 pmid: 18424132
[52]	Milton, N.; Moder, K. P.; Sabatowski, J. L.; Sweetana, S. A. WO 0051564, 2000.
[53]	Hughes, D.; Hughes, M.; Hughes, R.; Radhakrishnan, B.; Borguet, Y.; McIntyre, S.WO 2019241626, 2019.
[54]	(a) Cheung, Y. Y.; Hui, M. Antimicrob. Agents Chemother. 2017, 61, e00619-17.
	(b) Verweer, P. E.; Van Duijn, M. L.; Tavakol, M.; Bakker-Woudenberg, I. A.; Van De Sande, W. W. Antimicrob. Agents Chemother. 2012, 56, 1595.
	(c) Smith, J. D.; Johnson, R. L. Antimicrob. Agents Chemother. 2003, 47, 1452.
[55]	(a) Fazakerley, N. J.; Procter, D. J. Tetrahedron 2014, 70, 6911.
	(b) Goethe, O.; Heuer, A.; Ma, X.; Wang, Z.; Herzon, S. B. Nat. Prod. Rep. 2019, 36, 220.
	(c) Davidovich, C.; Bashan, A.; Auerbach-Nevo, T.; Yonath, A. Proc. Natl. Acad. Sci. U. S. A. 2007, 104, 4291.
	(d) Paukner, S.; Riedl, R. Cold Spring Harbor Perspect. Med. 2017, 7, a027110.
	(e) Gentry, D. R.; Rittenhouse, S. F.; McCloskey, L.; Holmes, D. J. Antimicrob. Agents Chemother. 2007, 51, 2048.
[56]	(a) Mu, W.-Y.; Liu, Z.-D. CN 103450060, 2013.
	(b) Shang, R.-F.; Liu, Y.; Yi, Y.-P.; Hao, B.-C.; Yang, Z.; Liang, J.-P. CN 107759502, 2019.
[57]	(a) Xie, C.-X.; Liu, Y.-T.; Deng, W.-K.; Wang, P.-F. CN 101880252, 2010.
	(b) Huang, K.; Li, J.-M.; Zhang, Y.; Jia, G.-B.; Yuan, Q.-X.; Guo, J.-L.; Wei, Y.-H.; Kong, R.-G.; Du, Y.-J. CN 106432017, 2017.
[58]	(a) Feng, R.-J.; Shi, Y.-L.; Wu, Y.-W.; Bei, R.-B.; Chen, H.-L. CN 105037348, 2015.
	(b) Wang, F.; Zhan, X.; He, Z.-H.; Wang, S.-H.; Chen, X.-Z.; Yang, Y.-J. CN 107235971, 2017.
[59]	(a) Heilmayer, W.; Mang, R.; Badegruber, R.; Stickmann, D.; Novak, R.; Ferencic, M.; Bulusu, A. R. C. M. MX 2010009451, 2012.
	(b) Mang, R.; Heilmayer, W.; Spence, L.EP 2399904, 2011.
[60]	(a) Murphy, S. K.; Zeng, M.; Herzon, S. B. Science 2017, 356, 956.
	(b) Goethe, O.; DiBello, M.; Herzon, S. B. Nat. Chem. 2022, 14, 1270.
[61]	(a) Lamoth, F.; Alexander, B. D. Antimicrob. Agents Chemother. 2015, 59, 4308.
	(b) Scorneaux, B.; Angulo, D.; Borroto-Esoda, K.; Ghannoum, M.; Peel, M.; Wring, S. Antimicrob. Agents Chemother. 2017, 61, e01961.