药学学报, 2019, 54(9): 1554-1563
引用本文:
鲁海嘉, 张东峰, 黄海洪. 抗革兰氏阴性菌药物的研究进展[J]. 药学学报, 2019, 54(9): 1554-1563.
LU Hai-jia, ZHANG Dong-feng, HUANG Hai-hong. Recent advances in study of drugs against Gram-negative pathogens[J]. Acta Pharmaceutica Sinica, 2019, 54(9): 1554-1563.

抗革兰氏阴性菌药物的研究进展
鲁海嘉, 张东峰, 黄海洪
中国医学科学院、北京协和医学院药物研究所, 活性物质发现与适药化研究北京市重点实验室, 北京 100050
摘要:
抗生素在临床上的长期使用导致细菌发生变异和耐药,另外,抗生素在医疗及农业领域的过度使用或不当使用加剧细菌耐药性的发生。2017年世界卫生组织首次公布了最需要新抗生素的12种细菌和细菌家族清单,其中9种为革兰氏阴性菌。革兰氏阴性菌具有多层结构的细胞壁,这种特殊的结构导致许多抗生素不能通过革兰氏阴性菌的外膜到达靶点,因此,抗革兰氏阴性菌的药物研发难度巨大,过去50年来,还没有针对革兰氏阴性菌的新机制抗生素获得批准。本文简要综述了目前不同作用机制下抗革兰氏阴性菌药物的研究进展。
关键词:    革兰氏阴性菌      耐药      作用机制      抗菌药物     
Recent advances in study of drugs against Gram-negative pathogens
LU Hai-jia, ZHANG Dong-feng, HUANG Hai-hong
Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100050, China
Abstract:
The long-term use of antibiotics in clinical practice leads to bacterial variation and resistance. In addition, the excessive or improper use of antibiotics in medical and agricultural fields increases the occurrence of bacterial resistance. In 2017, the World Health Organization has for the first time released a list of 12 bacteria or bacterial families that pose the greatest threat to human health and for which new antibiotics are desperately needed, and three quarters of them are Gram-negative bacteria. Gram-negative bacteria has multi-layered cell wall that prevents many antibiotics from accessing their targets. Therefore, it is very difficult to develop drugs against Gram-negative bacteria, no new class of antibiotic has been approved for Gram-negative pathogens in over fifty years. Here, we summarized recent advances in the study of new antibacterial agents with different mechanisms of action against Gram-negative pathogens.
Key words:    Gram-negative bacteria    drug resistance    mechanism of action    antibiotics   
收稿日期: 2019-06-11
DOI: 10.16438/j.0513-4870.2019-0467
通讯作者: 张东峰,Tel:86-10-63165254,E-mail:zdf@imm.ac.cn
Email: zdf@imm.ac.cn
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参考文献:
[1] World Health Organization. WHO publishes list of bacteria for which new antibiotics are urgently needed[N]. Geneva:WHO, 2017.
[2] Narita S. ABC transporters involved in the biogenesis of the outer membrane in gram-negative bacteria[J]. Biosci Biotechnol Biochem, 2011, 75:1044-1054.
[3] McLeod SM, Fleming PR, MacCormack K, et al. Small-molecule inhibitors of gram-negative lipoprotein trafficking discovered by phenotypic screening[J]. J Bacteriol, 2015, 197:1075-1082.
[4] Nayar AS, Dougherty TJ, Ferguson KE, et al. Novel antibacterial targets and compounds revealed by a high-throughput cell wall reporter assay[J]. J Bacteriol, 2015, 197:1726-1734.
[5] Nickerson NN, Jao CC, Xu Y, et al. A novel inhibitor of the LolCDE ABC transporter essential for lipoprotein trafficking in gram-negative bacteria[J]. Antimicrob Agents Chemother, 2018, 62:e02151-17.
[6] Sperandeo P, Lau FK, Carpentieri A, et al. Functional analysis of the protein machinery required for transport of lipopolysaccharide to the outer membrane of Escherichia coli[J]. J Bacteriol, 2008, 190:4460-4469.
[7] Laguri C, Sperandeo P, Pounot K, et al. Interaction of lipopolysaccharides at intermolecular sites of the periplasmic Lpt transport assembly[J]. Sci Rep, 2017, 7:9715.
[8] Luo Q, Yang X, Yu S, et al. Structural basis for lipopolysaccharide extraction by ABC transporter LptB2FG[J]. Nat Struct Mol Biol, 2017, 24:469-474.
[9] May JM, Owens TW, Mandler MD, et al. The antibiotic novobiocin binds and activates the ATPase that powers lipopolysaccharide transport[J]. J Am Chem Soc, 2017, 139:17221-17224.
[10] Hicks G, Jia Z. Structural basis for the lipopolysaccharide export activity of the bacterial lipopolysaccharide transport system[J]. Int J Mol Sci, 2018, 19:E2680.
[11] Narita S, Tokuda H. Biochemical characterization of an ABC transporter LptBFGC complex required for the outer membrane sorting of lipopolysaccharides[J]. FEBS Lett, 2009, 583:2160-2164.
[12] Sperandeo P, Villa R, Martorana AM, et al. New insights into the Lpt machinery for lipopolysaccharide transport to the cell surface:LptA-LptC interaction and LptA stability as sensors of a properly assembled transenvelope complex[J]. J Bacteriol, 2011, 193:1042-1053.
[13] Suits MD, Sperandeo P, Deho G, et al. Novel structure of the conserved gram-negative lipopolysaccharide transport protein A and mutagenesis analysis[J]. J Mol Biol, 2008, 380:476-488.
[14] Qiao S, Luo Q, Zhao Y, et al. Structural basis for lipopolysaccharide insertion in the bacterial outer membrane[J]. Nature, 2014, 511:108-111.
[15] Chng SS, Ruiz N, Chimalakonda G, et al. Characterization of the two-protein complex in Escherichia coli responsible for lipopolysaccharide assembly at the outer membrane[J]. Proc Natl Acad Sci U S A, 2010, 107:5363-5368.
[16] Freinkman E, Chng SS, Kahne D. The complex that inserts lipopolysaccharide into the bacterial outer membrane forms a two-protein plug-and-barrel[J]. Proc Natl Acad Sci U S A, 2011, 108:2486-2491.
[17] Zhang X, Li Y, Wang W, et al. Identification of an anti-gram-negative bacteria agent disrupting the interaction between LPS transporters LptA and LptC[J]. Int J Antimicrob Agents, 2019, 53:442-448.
[18] Srinivas N, Jetter P, Ueberbacher BJ, et al. Peptidomimetic antibiotics target outer-membrane biogenesis in Pseudomonas aeruginosa[J]. Science, 2010, 327:1010-1013.
[19] Werneburg M, Zerbe K, Juhas M, et al. Inhibition of lipopolysaccharide transport to the outer membrane in Pseudomonas aeruginosa by peptidomimetic antibiotics[J]. ChemBioChem, 2012, 13:1767-1775.
[20] Takayama K, Qureshi N, Mascagni P, et al. Fatty acyl derivatives of glucosamine 1-phosphate in Escherichia coli and their relation to lipid A. Complete structure of a diacyl GlcN-1-P found in a phosphatidylglycerol-deficient mutant[J]. J Biol Chem, 1983, 258:7379-7385.
[21] Anderson MS, Bulawa CE, Raetz CR. The biosynthesis of gram-negative endotoxin. Formation of lipid A precursors from UDP-GlcNAc in extracts of Escherichia coli[J]. J Biol Chem, 1985, 260:15536-15541.
[22] Crowell DN, Anderson MS, Raetz CR. Molecular cloning of the genes for lipid A disaccharide synthase and UDP-N-acetylglucosamine acyltransferase in Escherichia coli[J]. J Bacteriol, 1986, 168:152-159.
[23] Tomaras AP, McPherson CJ, Kuhn M, et al. LpxC inhibitors as new antibacterial agents and tools for studying regulation of lipid A biosynthesis in gram-negative pathogens[J]. mBio, 2014, 5:1-13.
[24] Barsotti RJ, Macy NE, Aubart MA, et al. Impact resistant transparent thermoplastic compositions:WO, 2014062601[P].2014-04-24.
[25] Titecat M, Liang X, Lee CJ, et al. High susceptibility of MDR and XDR gram-negative pathogens to biphenyl-diacetylene-based difluoromethyl-allo-threonyl-hydroxamate LpxC inhibitors[J]. J Antimicrob Chemother, 2016, 71:2874-2882.
[26] Zhou P, Zhao J. Structure, inhibition, and regulation of essential lipid A enzymes[J]. Biochim Biophys Acta, 2017, 1862:1424-1438.
[27] Montgomery JI,Brown MF, Reilly U, et al. Pyridone methylsulfone hydroxamate LpxC inhibitors for the treatment of serious gram-negative infections[J]. J Med Chem, 2012, 55:1662-1670.
[28] Kalinin DV, Holl R. LpxC inhibitors:a patent review (2010-2016)[J]. Expert Opin Ther Pat, 2017, 27:1227-1250.
[29] Desroy N, Moreau F, Briet S, et al. Towards gram-negative antivirulence drugs:new inhibitors of HldE kinase[J]. Bioorg Med Chem, 2009, 17:1276-1289.
[30] Moreau F, Desroy N, Genevard JM, et al. Discovery of new gram-negative antivirulence drugs:structure and properties of novel E. coli WaaC inhibitors[J]. Bioorg Med Chem Lett, 2008, 18:4022-4026.
[31] Desroy N, Denis A, Oliveira C, et al. Novel HldE-K inhibitors leading to attenuated gram negative bacterial virulence[J]. J Med Chem, 2013, 56:1418-1430.
[32] Champoux JJ. DNA topoisomerases:structure, function, and mechanism[J]. Annu Rev Biochem, 2001, 70:369-413.
[33] Schoeffler AJ, Berger JM. DNA topoisomerases:harnessing and constraining energy to govern chromosome topology[J]. Q Rev Biophys, 2008, 41:41-101.
[34] Tari LW, Li X, Trzoss M, et al. Tricyclic GyrB/ParE (TriBE) inhibitors:a new class of broad-spectrum dual-targeting antibacterial agents[J]. PLoS One, 2013, 8:e84409.
[35] de Souza Mendes C, de Souza Antunes AM. Pipeline of known chemical classes of antibiotics[J]. Antibiotics (Basel), 2013, 2:500-534.
[36] Azam MA, Thathan J, Jubie S. Dual targeting DNA gyrase B (GyrB) and topoisomerse IV (ParE) inhibitors:a review[J]. Bioorg Chem, 2015, 62:41-63.
[37] Morrow BJ, He W, Amsler KM, et al. In vitro antibacterial activities of JNJ-Q2, a new broad-spectrum fluoroquinolone[J]. Antimicrob Agents Chemother, 2010, 54:1955-1964.
[38] Chu DT, Fernandes PB, Claiborne AK, et al. Structure-activity relationships in quinolone antibacterials:design, synthesis and biological activities of novel isothiazoloquinolones[J]. Drugs Exp Clin Res, 1988, 14:379-383.
[39] Chu DT, Lico IM, Claiborne AK, et al. Structure-activity relationship of quinolone antibacterial agents:the effects of C-2 substitution[J]. Drugs Exp Clin Res, 1990, 16:215-224.
[40] Pucci MJ, Podos SD, Thanassi JA, et al. In vitro and in vivo profiles of ACH-702, an isothiazoloquinolone, against bacterial pathogens[J]. Antimicrob Agents Chemother, 2011, 55:2860-2871.
[41] Bax BD, Chan PF, Eggleston DS, et al. Type ⅡA topoisomerase inhibition by a new class of antibacterial agents[J]. Nature, 2010, 466:935-940.
[42] Dougherty TJ, Nayar A, Newman JV, et al. NBTI 5463 is a novel bacterial type Ⅱ topoisomerase inhibitor with activity against gram-negative bacteria and in vivo efficacy[J]. Antimicrob Agents Chemother, 2014, 58:2657-2664.
[43] Basarab GS, Doig P, Galullo V, et al. Discovery of novel DNA gyrase inhibiting spiropyrimidinetriones:benzisoxazole fusion with N-linked oxazolidinone substituents leading to a clinical candidate (ETX0914)[J]. J Med Chem, 2015, 58:6264-6282.
[44] Basarab GS, Kern GH, McNulty J, et al. Responding to the challenge of untreatable gonorrhea:ETX0914, a first-in-class agent with a distinct mechanism-of-action against bacterial Type Ⅱ topoisomerases[J]. Sci Rep, 2015, 5:11827.
[45] Haranahalli K, Tong S, Ojima I. Recent advances in the discovery and development of antibacterial agents targeting the cell-division protein FtsZ[J]. Bioorg Med Chem, 2016, 24:6354-6369.
[46] Ma S, Ma S. The development of FtsZ inhibitors as potential antibacterial agents[J]. ChemMedChem, 2012, 7:1161-1172.
[47] Hogan AM, Scoffone VC, Makarov V, et al. Competitive fitness of essential gene knockdowns reveals a broad-spectrum antibacterial inhibitor of the cell division protein FtsZ[J]. Antimicrob Agents Chemother, 2018, 62:e01231-18.
[48] Sun N, Ban L, Li M, et al. Probing the benzofuroquinolinium derivative as a potent antibacterial agent through the inhibition of FtsZ activity[J]. J Pharmacol Sci, 2018, 138:83-85.
[49] Bush K, Bradford PA. Beta-lactams and beta-lactamase inhibitors:an overview[J]. Cold Spring Harb Perspect Med, 2016, 6:a025247.
[50] Pattanaik P, Bethel CR, Hujer AM, et al. Strategic design of an effective beta-lactamase inhibitor:LN-1-255, a 6-alkylidene-2'-substituted penicillin sulfone[J]. J Biol Chem, 2009, 284:945-953.
[51] Vázquez-Ucha JC, Maneiro M, Martínez-Guitián M, et al. Activity of the β-lactamase inhibitor LN-1-255 against carbapenem-hydrolyzing class D β-lactamases from Acinetobacter baumannii[J]. Antimicrob Agents Chemother, 2017, 61:e01172-17.
[52] Docquier JD, Mangani S. An update on beta-lactamase inhibitor discovery and development[J]. Drug Resist Updat, 2018, 36:13-29.
[53] Zhanel GG, Lawrence CK, Adam H, et al. Imipenem-relebactam and meropenem-vaborbactam:two novel carbapenem-beta-lactamase inhibitor combinations[J]. Drugs, 2018, 78:65-98.
[54] McCarthy MW, Walsh TJ. Meropenem/vaborbactam fixed combination for the treatment of patients with complicated urinary tract infections[J]. Drugs Today (Barc), 2017, 53:521-530.
[55] Lee YR, Baker NT. Meropenem-vaborbactam:a carbapenem and beta-lactamase inhibitor with activity against carbapenem-resistant Enterobacteriaceae[J]. Eur J Clin Microbiol Infect Dis, 2018, 37:1411-1419.
[56] Font H, Forner DF. American chemical society-255th national meeting and exhibition[J]. Drugs of the Future, 2018, 43:365-373.
[57] Burns CJ, Daigle D, Liu B, et al. Beta-lactamase inhibitors:WO, 2014089365[P]. 2014-06-12.
[58] Rao CVS, De Waelheyns E, Economou A, et al. Antibiotic targeting of the bacterial secretory pathway[J]. Biochim Biophys Acta, 2014, 1843:1762-1783.
[59] Smith PA, Koehler MFT, Girgis HS, et al. Optimized arylomycins are a new class of gram-negative antibiotics[J]. Nature, 2018, 561:189-194.
[60] Chu BC, Garcia-Herrero A, Johanson TH, et al. Siderophore uptake in bacteria and the battle for iron with the host; a bird's eye view[J]. BioMetals, 2010, 23:601-611.
[61] Ji C, Juarez-Hernandez RE, Miller MJ. Exploiting bacterial iron acquisition:siderophore conjugates[J]. Future Med Chem, 2012, 4:297-313.
[62] Mollmann U, Heinisch L, Bauernfeind A, et al. Siderophores as drug delivery agents:application of the "Trojan Horse" strategy[J]. BioMetals, 2009, 22:615-624.
[63] Isler B, Doi Y, Bonomo RA, et al. New treatment options against carbapenem-resistant Acinetobacter baumannii infections[J]. Antimicrob Agents Chemother, 2019, 63:e01110-18.
[64] Page MG, Heim J. New molecules from old classes:revisiting the development of beta-lactams[J]. IDrugs, 2009, 12:561-565.
[65] 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.
[66] Bush K. Investigational agents for the treatment of gram-negative bacterial infections:a reality check[J]. ACS Infect Dis, 2015, 1:509-511.
[67] Tan L, Tao Y, Wang T, et al. Discovery of novel pyridone-conjugated monosulfactams as potent and broad-spectrum antibiotics for multidrug-resistant gram-negative infections[J]. J Med Chem, 2017, 60:2669-2684.
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