药学学报, 2021, 56(11): 3004-3013
引用本文:
赵欣彤, 李天磊, 张文轩*, 吴松*. 铁离子载体-抗生素偶联物的研究进展[J]. 药学学报, 2021, 56(11): 3004-3013.
ZHAO Xin-tong, LI Tian-lei, ZHANG Wen-xuan*, WU Song*. Research progress on siderophore-antibiotic conjugates[J]. Acta Pharmaceutica Sinica, 2021, 56(11): 3004-3013.

铁离子载体-抗生素偶联物的研究进展
赵欣彤, 李天磊, 张文轩*, 吴松*
中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050
摘要:
随着细菌耐药特别是革兰阴性细菌耐药趋势的不断上升,耐药细菌的感染已成为临床最难解决的问题之一。基于“特洛伊木马”策略设计的铁载体-抗生素偶联物,可以通过主动摄取穿过革兰阴性细菌的外膜,有望成为临床抗感染治疗的有力武器。本文回顾了近年来报道的铁载体-抗生素偶联物药物设计策略,并重点探讨了不同类型的抗生素在此策略中的使用。
关键词:    铁离子载体      铁离子载体-抗生素偶联物      革兰阴性菌      抗生素耐药     
Research progress on siderophore-antibiotic conjugates
ZHAO Xin-tong, LI Tian-lei, ZHANG Wen-xuan*, WU Song*
State Key Laboratory of Natural Medicine Active Substances and Functions, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
Abstract:
With the increasing drug resistance of bacteria, especially Gram-negative bacteria, the infection of drug-resistant bacteria has become one of the most challengeable clinical problems. The siderophore-antibiotic conjugates based on the "Trojan horse" strategy can penetrate the extracellular membrane of Gram-negative bacteria by active transport, and they are expected to become a powerful weapon for clinical anti-infection treatment. This review describes the drug design strategies of siderophore-antibiotic conjugates reported in recent years, and focuses on the use of different types of antibiotics in this strategy.
Key words:    siderophore    siderophore-antibiotic conjugate    Gram-negative bacteria    antibiotic resistance   
收稿日期: 2021-03-23
DOI: 10.16438/j.0513-4870.2021-0410
基金项目: “重大新药创制”国家科技重大专项(2018ZX09711001-005);中国医学科学院医学与健康科技创新工程重大项目(2017-I2M-2-004).
通讯作者: 张文轩,Tel:86-10-83163542,E-mail:wxzhang@imm.ac.cn;吴松,E-mail:ws@imm.ac.cn
Email: wxzhang@imm.ac.cn;ws@imm.ac.cn
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参考文献:
[1] Willyard C. The drug-resistant bacteria that pose the greatest health threats[J]. Nature, 2017, 543: 15.
[2] Lewis K. Platforms for antibiotic discovery[J]. Nat Rev Drug Discov, 2013, 12: 371-387.
[3] Lin J, Nishino K, Roberts MC, et al. Mechanisms of antibiotic resistance[J]. Front Microbiol, 2015, 6: 34.
[4] Lu HJ, Zhang DF, Huang HH. Recent advances in study of drugs against Gram-negative pathogens[J]. Acta Pharm Sin (药学学报), 2019, 54: 1554-1563.
[5] Zgurskaya HI, Lopez CA, Gnanakaran S. Permeability barrier of Gram-negative cell envelopes and approaches to bypass it[J]. ACS Infect Dis, 2015, 1: 512-522.
[6] Ji C, Juárez-Hernández RE, Miller MJ. Exploiting bacterial iron acquisition: siderophore conjugates[J]. Future Med Chem, 2012, 4: 297-313.
[7] Pagès JM, James CE, Winterhalter M. The porin and the permeating antibiotic: a selective diffusion barrier in Gram-negative bacteria[J]. Nat Rev Drug Discov, 2008, 6: 893-903.
[8] Hancock REW. The bacterial outer membrane as a drug barrier[J]. Trends Microbiol, 1997, 5: 37-42.
[9] Jordi V, Sara M, Javier SC. Porins, efflux pumps and multidrug resistance in Acinetobacter baumannii[J]. J Antimicrob Chemother, 2007, 59: 1210-1215.
[10] Taylor KG, Konhauser KO. Iron in earth surface systems: a major player in chemical and biological processes[J]. Elements, 2011, 7: 83-88.
[11] Wilson BR, Bogdan AR, Miyazawa M, et al. Siderophores in iron metabolism: from mechanism to therapy potential[J]. Trends Mol Med, 2016, 22: 1077-1090.
[12] Soares MP, Weiss G. The iron age of host-microbe interactions[J]. Embo Reports, 2015, 16: 1482-1500.
[13] Braun V, Killmann H. Bacterial solutions to the iron-supply problem[J]. Trends Biochem Sci, 1999, 24: 104-109.
[14] Hider RC, Kong X. Chemistry and biology of siderophores[J]. Nat Prod Rep, 2010, 27: 637-657.
[15] Raymond KN, Allred BE, Sia AK. Coordination chemistry of microbial iron transport[J]. Acc Chem Res, 2015, 48: 2496-2505.
[16] Raymond KN, Dertz EA, Kim SS. Enterobactin: an archetype for microbial iron transport[J]. Proc Natl Acad Sci U S A, 2003, 100: 3584-3588.
[17] Hannauer M, Barda Y, Mislin GL, et al. The ferrichrome uptake pathway in Pseudomonas aeruginosa involves an iron release mechanism with acylation of the siderophore and recycling of the modified desferrichrome[J]. J Bacteriol, 2010, 192: 1212-1220.
[18] Schlegel K, Lex J, Taraz K, et al. The X-ray structure of the pyochelin Fe3+ complex[J]. J Biosci, 2006, 61: 263-266.
[19] Modun B, Evans RW, Joannou CL, et al. Receptor-mediated recognition and uptake of iron from human transferrin by Staphylococcus aureus and Staphylococcus epidermidis[J]. Infect Immun, 1998, 66: 3591-3596.
[20] Gao Q, Wang X, Xu H, et al. Roles of iron acquisition systems in virulence of extraintestinal pathogenic Escherichia coli: salmochelin and aerobactin contribute more to virulence than heme in a chicken infection model[J]. BMC Microbiol, 2012, 12: 143.
[21] Schalk IJ, Guillon L. Fate of ferrisiderophores after import across bacterial outer membranes: different iron release strategies are observed in the cytoplasm or periplasm depending on the siderophore pathways[J]. Amino Acids, 2013, 44: 1267-1277.
[22] Roosenberg JM 2nd, Lin YM, Lu Y, et al. Studies and syntheses of siderophores, microbial iron chelators, and analogs as potential drug delivery agents[J]. Curr Med Chem, 2000, 7: 159-197.
[23] Negash KH, Norris JKS, Hodgkinson JT. Siderophore-antibiotic conjugate design: new drugs for bad bugs?[J]. Molecules, 2019, 24: 3314.
[24] Kong H, Cheng W, Wei H, et al. An overview of recent progress in siderophore-antibiotic conjugates[J]. Eur J Med Chem, 2019, 182: 111615.
[25] Braun V, Pramanik A, Gwinner T, et al. Sideromycins: tools and antibiotics[J]. Biometals, 2009, 22: 3-13.
[26] Gause FG. Recent studies on albomycin, a new antibiotic[J]. Br Med J, 1955, 2: 1177-1179.
[27] Braun V, Braun M. Active transport of iron and siderophore antibiotics[J]. Curr Opin Microbiol, 2002, 5: 194-201.
[28] Roosenberg JM, Miller MJ. Total synthesis of the siderophore danoxamine[J]. J Org Chem, 2000, 65: 4833-4838.
[29] Vértesy L, Aretz W, Fehlhaber HW, et al. Salmycin A-D, antibiotika aus Streptomyces violaceus, DSM 8286, mit siderophor‐aminoglycosid‐struktur[J]. Helv Chim Acta, 1995, 78: 46-60.
[30] Wencewicz TA, Mollmann U, Long TE, et al. Is drug release necessary for antimicrobial activity of siderophore-drug conjugates? Syntheses and biological studies of the naturally occurring salmycin "Trojan horse" antibiotics and synthetic desferridanoxamine-antibiotic conjugates[J]. Biometals, 2009, 22: 633-648.
[31] Brochu A, Brochu N, Nicas TI, et al. Modes of action and inhibitory activities of new siderophore-beta-lactam conjugates that use specific iron uptake pathways for entry into bacteria[J]. Antimicrob Agents Chemother, 1992, 36: 2166-2175.
[32] Lin YM, Ghosh M, Miller PA, et al. Synthetic sideromycins (skepticism and optimism): selective generation of either broad or narrow spectrum Gram-negative antibiotics[J]. Biometals, 2019, 32: 425-451.
[33] Dolence EK, Lin CE, Miller MJ, et al. Synthesis and siderophore activity of albomycin-like peptides derived from N5-acetyl-N5-hydroxy-L-ornithine[J]. J Med Chem, 1991, 34: 956-968.
[34] Ji C, Miller PA, Miller MJ. Iron transport-mediated drug delivery: practical syntheses and in vitro antibacterial studies of tris-catecholate siderophore-aminopenicillin conjugates reveals selectively potent antipseudomonal activity[J]. J Am Chem Soc, 2012, 134: 9898-9901.
[35] Zheng T, Nolan EM. Enterobactin-mediated delivery of beta-lactam antibiotics enhances antibacterial activity against pathogenic Escherichia coli[J]. J Am Chem Soc, 2014, 136: 9677-9691.
[36] Chairatana P, Zheng T, Nolan EM. Targeting virulence: salmochelin modification tunes the antibacterial activity spectrum of beta-lactams for pathogen-selective killing of Escherichia coli [J]. Chem Sci, 2015, 6: 4458-4471.
[37] Annamalai R, Jin B, Cao Z, et al. Recognition of ferric catecholates by FepA[J]. J Bacteriol, 2004, 186: 3578-3589.
[38] Ohi N, Aoki B, Shinozaki T, et al. Semisynthetic beta-lactam antibiotics. I. Synthesis and antibacterial activity of new ureidopenicillin derivatives having catechol moieties[J]. J Antibiot, 1986, 39: 230-241.
[39] Ito A, Nishikawa T, Matsumoto S, et al. Siderophore cephalosporin cefiderocol utilizes ferric iron transporter systems for antibacterial activity against Pseudomonas aeruginosa[J]. Antimicrob Agents Chemother, 2016, 60: 7396-7401.
[40] Page MGP. The role of iron and siderophores in infection, and the development of siderophore antibiotics[J]. Clin Infect Dis, 2019, 69: S529-S537.
[41] Ito A, Sato T, Ota M, et al. In vitro antibacterial properties of cefiderocol, a novel siderophore cephalosporin, against Gram-negative bacteria[J]. Antimicrob Agents Chemother, 2018, 62: e01454-17.
[42] Zhanel GG, Golden AR, Zelenitsky S, et al. Cefiderocol: a siderophore cephalosporin with activity against carbapenem-resistant and multidrug-resistant Gram-negative bacilli[J]. Drugs, 2019, 79: 271-289.
[43] Sykes RB, Koster WH, Bonner DP. The new monobactams: chemistry and biology[J]. J Clin Pharmacol, 1988, 28: 113-119.
[44] Michael R, Terrence C. Synthesis and structure-activity relationships of monocarbams leading to U-78608[J]. J Antibiot, 1990, 43: 1199-1203.
[45] Flanagan ME, Brickner SJ, Lall M, et al. Preparation, Gram-negative antibacterial activity, and hydrolytic stability of novel siderophore-conjugated monocarbam diols[J]. ACS Med Chem Lett, 2011, 2: 385-390.
[46] McPherson CJ, Aschenbrenner LM, Lacey BM, et al. Clinically relevant Gram-negative resistance mechanisms have no effect on the efficacy of MC-1, a novel siderophore-conjugated monocarbam[J]. Antimicrob Agents Chemother, 2012, 56: 6334-6342.
[47] Tomaras AP, Crandon JL, McPherson CJ, et al. Potentiation of antibacterial activity of the MB-1 siderophore-monobactam conjugate using an efflux pump inhibitor[J]. Antimicrob Agents Chemother, 2015, 59: 2439-2442.
[48] Page MG, Dantier C, Desarbre E. In vitro properties of BAL30072, a novel siderophore sulfactam with activity against multiresistant gram-negative bacilli[J]. Antimicrob Agents Chemother, 2010, 54: 2291-2302.
[49] Schalk IJ, Mislin GLA. Bacterial iron uptake pathways: gates for the import of bactericide compounds[J]. J Med Chem, 2017, 60: 4573-4576.
[50] Rivault F, Liébert C, Burger A, et al. Synthesis of pyochelin-norfloxacin conjugates[J]. Bioorg Med Chem Lett, 2007, 17: 640-644.
[51] Neumann W, Nolan EM. Evaluation of a reducible disulfide linker for siderophore-mediated delivery of antibiotics[J]. J Biol Inorg Chem, 2018, 23: 1025-1036.
[52] Neumann W, Sassone-Corsi M, Raffatellu M, et al. Esterase-catalyzed siderophore hydrolysis activates an enterobactin-ciprofloxacin conjugate and confers targeted antibacterial activity[J]. J Am Chem Soc, 2018, 140: 5193-5201.
[53] Zheng T, Nolan EM. Evaluation of (acyloxy)alkyl ester linkers for antibiotic release from siderophore-antibiotic conjugates[J]. Bioorg Med Chem Lett, 2015, 25: 4987-4991.
[54] Ji C, Miller MJ. Chemical syntheses and in vitro antibacterial activity of two desferrioxamine B-ciprofloxacin conjugates with potential esterase and phosphatase triggered drug release linkers[J]. Biorg Med Chem, 2012, 20: 3828-3836.
[55] Paulen A, Gasser V, Hoegy F, et al. Synthesis and antibiotic activity of oxazolidinone-catechol conjugates against Pseudomonas aeruginosa[J]. Org Biomol Chem, 2015, 13: 11567-11579.
[56] Noël S, Gasser V, Pesset B, et al. Synthesis and biological properties of conjugates between fluoroquinolones and a N3''-functionalized pyochelin[J]. Org Biomol Chem, 2011, 9: 8288.
[57] Ji C, Miller MJ. Siderophore-fluoroquinolone conjugates containing potential reduction-triggered linkers for drug release: synthesis and antibacterial activity[J]. Biometals, 2015, 28: 541-551.
[58] Fardeau S, Dassonville-Klimpt A, Audic N, et al. Synthesis and antibacterial activity of catecholate-ciprofloxacin conjugates[J]. Bioorg Med Chem, 2014, 22: 4049-4060.
[59] Barbachyn, Michael R. Antibacterials[M]. Cham: Springer International Publishing, 2018: 97-121.
[60] Paulen A, Fo Hoegy, Roche B, et al. Synthesis of conjugates between oxazolidinone antibiotics and a pyochelin analogue[J]. Bioorg Med Chem Lett, 2017, 27: 4867-4870.
[61] Liu R, Miller PA, Vakulenko SB, et al. A synthetic dual drug sideromycin induces Gram-negative bacteria to commit suicide with a Gram-positive antibiotic[J]. J Med Chem, 2018, 61: 3845-3854.
[62] Miller MJ, Walz AJ, Zhu H, et al. Design, synthesis, and study of a mycobactin-artemisinin conjugate that has selective and potent activity against tuberculosis and malaria[J]. J Am Chem Soc, 2011, 133: 2076-2079.
[63] Ghosh M, Miller PA, Mollmann U, et al. Targeted antibiotic delivery: selective siderophore conjugation with daptomycin confers potent activity against multidrug resistant acinetobacter baumannii both in vitro and in vivo[J]. J Med Chem, 2017, 60: 4577-4583.
[64] Ghosh M, Miller PA, Miller MJ. Antibiotic repurposing: bis-catechol- and mixed ligand (bis-catechol-mono-hydroxamate)-teicoplanin conjugates are active against multidrug resistant Acinetobacter baumannii[J]. J Antibiot (Tokyo), 2020, 73: 152-157.
[65] Nagy TA, Moreland SM, Andrews-Polymenis H, et al. The ferric enterobactin transporter Fep is required for persistent Salmonella enterica serovar Typhimurium infection[J]. Infect Immun, 2013, 81: 4063-4070.
[66] Caza M, Lepine F, Dozois CM. Secretion, but not overall synthesis, of catecholate siderophores contributes to virulence of extraintestinal pathogenic Escherichia coli[J]. Mol Microbiol, 2011, 80: 266-282.
[67] Crouch ML, Castor M, Karlinsey JE, et al. Biosynthesis and IroC-dependent export of the siderophore salmochelin are essential for virulence of Salmonella enterica serovar Typhimurium[J]. Mol Microbiol, 2008, 67: 971-983.