抗结核药物作用新靶点及其研究进展

doi:10.3969/j.issn.1000-6621.2020.03.020

摘要/Abstract

摘要：

结核病是威胁我国乃至全世界的健康问题。由于细菌变异、治疗方案不合理和药物滥用等原因导致细菌耐药情况越来越严重,耐药结核病已经威胁到了全人类的健康安全。近10年来针对结核分枝杆菌各种新靶点的抗结核新药已经陆续进入临床试验,作者对抗结核分枝杆菌研究中细胞壁合成、蛋白质合成和能量代谢机制的新靶点进行梳理和分析,并且对一些相关的新型化合物进行简要介绍,以期为抗结核药物的研发提供参考。

关键词: 抗结核药, 新靶点, 新型化合物, 研究进展

Abstract:

Tuberculosis remains a health problem that threatens our country and the world. Bacterial resistance is becoming more and more serious due to bacterial mutations, irrational treatment options, and drug abuse, and drug-resistant tuberculosis has threatened the health and safety of all human beings. In the past decade,many new anti-tuberculosis drugs targeting various new targets of Mycobacterium tuberculosis have been gradually started clinical trials. This review analyzes the new targets for cell wall synthesis, protein synthesis and energy metabolism in the study of anti-Mycobacterium tuberculosis and briefly introduce some related new compounds,in order to provide reference for the development of anti-tuberculosis drugs.

Key words: Antitubercular agents, New targets, Novel compounds, Research progress

陈浩,武楠楠,胡文辉,杨忠金. 抗结核药物作用新靶点及其研究进展[J]. 中国防痨杂志, 2020, 42(3): 286-292. doi: 10.3969/j.issn.1000-6621.2020.03.020

CHEN Hao,WU Nan-nan,HU Wen-hui,YANG Zhong-jin. Research progress of new targets for antituberculosis agents[J]. Chinese Journal of Antituberculosis, 2020, 42(3): 286-292. doi: 10.3969/j.issn.1000-6621.2020.03.020

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参考文献 37

[1]	Global tuberculosis report 2019. Guidelines for treatment of drug-susceptible tuberculosis and patient care. Geneva: World Health Organization, 2017.
[2]	Tiberi S, Muñoz-Torrico M, Duarte R , et al. New drugs and perspectives for new anti-tuberculosis regimens. Pulmonology, 2018,24(2):86-98.
[3]	Peng CT, Gao C, Wang NY , et al. Synthesis and antitubercular evaluation of 4-carbonyl piperazine substituted 1,3-benzothiazin-4-one derivatives. Bioorg Med Chem Lett, 2015,25(7):1373-1376.
[4]	Trefzer C, Škovierová H, Buroni S , et al. Benzothiazinones Are Suicide Inhibitors of Mycobacterial Decaprenylphosphoryl-β-d-ribofuranose 2'-Oxidase DprE1. J Am Chem Soc, 2012,134(2):912-915.
[5]	Evans JC, Mizrahi V . Priming the tuberculosis drug pipeline: new antimycobacterial targets and agents. Curr Opin Microbiol, 2018,45:39-46.
[6]	Xu Z, Meshcheryakov VA, Poce G , et al. MmpL3 is the flippase for mycolic acids in mycobacteria. Proc Natl Acad Sci U S A, 2017,114(30):7993-7998.
[7]	Li W, Obregon-Henao A, Wallach JB , et al. Therapeutic Potential of the Mycobacterium tuberculosis Mycolic Acid Transporter, MmpL3. Antimicrob Agents Chemother, 2016,60(9):5198-5207.
[8]	Tahlan K, Wilson R, Kastrinsky DB , et al. SQ109 Targets MmpL3, a Membrane Transporter of Trehalose Monomycolate Involved in Mycolic Acid Donation to the Cell Wall Core of Mycobacterium tuberculosis. Antimicrobial Agents and Chemotherapy, 2012,56(4):1797-1809.
[9]	Mukherjee T, Boshoff H . Nitroimidazoles for the treatment of TB: past, present and future. Future Med Chem, 2011,3(11):1427-1454.
[10]	Manjunatha U, Boshoff HI, Barry CE . The mechanism of action of PA-824: Novel insights from transcriptional profiling. Commun Integr Biol, 2009,2(3):215-218.
[11]	Matsumoto M, Hashizume H, Tomishige T , et al. OPC-67683, a nitro-dihydroimidazooxazole derivative with promi-sing action against tuberculosis in vitro and in mice. PLoS Med, 2006,3(11):e466.
[12]	Global tuberculosis report 2019. The Use of Delamanid in the Treatment of Multidrug-Resistant Tuberculosisin Children and Adolescents: Interim Policy Guidance. Geneva: World Health Organization, 2016.
[13]	Baptista R, Fazakerley DM, Beckmann M , et al. Untargeted metabolomics reveals a new mode of action of pretomanid (PA-824). Sci Rep, 2018,8(1):5084.
[14]	Lenaerts AJ, Gruppo V, Marietta KS , et al. Preclinical Testing of the Nitroimidazopyran PA-824 for Activity against Mycobacterium tuberculosis in a Series of In Vitro and In Vivo Models. Antimicrob Agents Chemotherapy, 2005,49(6):2294-2301.
[15]	Diacon AH, Dawson R, du Bois J , et al. Phase Ⅱ Dose-Ranging Trial of the Early Bactericidal Activity of PA-824. Antimicrob Agents Chemotherapy, 2012,56(6):3027-3031.
[16]	Dawson R, Diacon AH, Everitt D , et al. Efficiency and safety of the combination of moxifloxacin, pretomanid(PA-824), and pyrazinamide during thefirst 8 weeks of antituberculosis treatment: a phase 2b, open-label, partly randomised trial in patients with drug-susceptible or drug-resistant pulmonary tuberculosis. Lancet, 2015,385(9979):1738-1747.
[17]	Makarov V, Manina G, Mikusova K , et al. Benzothiazinones Kill Mycobacterium tuberculosis by blocking arabinan synthesis. Science, 2009,324(5928):801-804.
[18]	Li L, Lv K, Yang Y , et al. Identificationof N-Benzyl 3,5-Dinitrobenzamides Derived from PBTZ169 as Antitubercular Agents. ACS Med Chem Lett, 2018,9(7):741-745.
[19]	Li K, Wang Y, Yang G , et al. Oxa, Thia,Heterocycle, and Carborane Analoguesof SQ109: Bacterial and ProtozoalCell Growth Inhibitors. ACS Infect Dis, 2015,1(5):215-221.
[20]	Chen P, Gearhart J, Protopopova M , et al. Synergistic interactions of SQ109, a new ethylene diamine, with front-line antitubercular drugs in vitro. J Antimicrob Chemother, 2006,58(2):332-337.
[21]	Infectex Announces Positive Phase 2b-3 Clinical Trial Results of SQ109 for the Treatment of Multidrug-Resistant Pulmonary Tuberculosis[EB/OL]. 2017- 03- 21. [2019-10-11]. http://www.sequella.com/docs/Infectex_PR_Mar2017.pdf .
[22]	Updates in the Development of Delamanid, OPC-167832, and Otsuka ’s LAM Biomarker[EB/OL]. [ 2019- 10- 11].http://www.cptrinitiative.org/wp-content/uploads/2017/05/Jeffrey_Hafkin_CPTR2017_JH.pdf .
[23]	Otsuka Awarded Grant to Advance Development of Novel Anti-Tuberculosis Compound OPC-167832 with Delamanid\|Business Wire[EB/OL]. 2018-01-29. [2019-10-11]. https://www.businesswire.com/news/home/20180129005073/en/Otsuka-Awarded-Grant-Advance-Development-Anti-Tuberculosis-Compound.
[24]	Working Group for New TB Drugs. TBA-7371[EB/OL].[2019-10-11]. https://www.newtbdrugs.org/pipeline/compound/tba-7371.
[25]	Jeong JW, Jung SJ, Lee HH , et al. In Vitro and In Vivo Activities of LCB01-0371, a New Oxazolidinone. Antimicrob Agents Chemother, 2010,54(12):5359-5362.
[26]	Li X, Hernandez V, Rock FL , et al. Discovery of a Potent and Specific M.tuberculosis Leucyl-tRNA Synthetase Inhibitor: (S)-3-(Aminomethyl)-4-chloro-7-(2-hydroxyethoxy) benzo[c][1,2]oxaborol-1(3H)-ol (GSK656). J Med Chem, 2017,60(19):8011-8026.
[27]	Yip PC, Kam KM, Lam ET , et al. In vitro activities of PNU-100480 and linezolid against drug-susceptible and drug-resis-tant Mycobacterium tuberculosis isolates. Int J Antimicrob Agents, 2013,42(1):96-97.
[28]	Wallis RS, Jakubiec W, Kumar V , et al. Biomarker-Assisted Dose Selection for Safety and Efficacy in Early Development of PNU-100480 for Tuberculosis. Antimicrob Agents Chemother, 2011,55(2):567-574.
[29]	Zong Z, Jing W, Shi J , et al. Comparison of In Vitro Activity and MIC Distributions between the Novel Oxazolidinone Delpazolid and Linezolid against Multidrug-Resistant and Extensively Drug-ResistantMycobacterium tuberculosis in China. Antimicrob Agents Chemother, 2018,62(5). pii: e00165-18.
[30]	Tenero D, Derimanov G, Carlton A , et al. First-Time-in-Human Study and Predict-ion of Early Bactericidal Activity for GSK3036656, a Potent Leucyl-tRNA Synthetase Inhibitor for Tuberculosis Treatment. Antimicrob Agents Chemother, 2019, 63(8). pii:e00240-19.
[31]	Bernard Fourie. The contribution of bedaquiline to the treatment of MDRTB.[C/OL].Geneva: WHO/STB Expert Group Meeting, 2013 [ 2019- 10- 11]. http://www.atsdr.cdc.gov/c95ab.html .
[32]	Kalia NP, Hasenoehrl EJ, Ab Rahman NB , et al. Exploiting the syntheticlethality between terminal respiratory oxidases to kill Mycobacterium tuberculosis and clear host infection. Proc Natl Acad Sci U S A, 2017,114(28):7426-7431.
[33]	Lechartier B, Cole ST . Mode of Action of Clofazimine and Combination Therapy with Benzothiazinones against Mycobacterium tuberculosis. Antimicrob Agents Chemother, 2015,59(8):4457-4463.
[34]	Erica Lessem,Lindsay McKenna. An Activist’s Guide to BEDAQUILINE (Sirturo) [EB/OL].[ 2019- 10- 11]. http://www.treatmentactiongroup.org/sites/default/files/BDQ_guide_10_5_18.pdf .
[35]	Global tuberculosis report 2019. The use of bedaquiline in the treatment of multidrug-resistant tuberculosis: interim policy guidance. Geneva:World Health Organization, 2013.
[36]	Pethe K, Bifani P, Jang J , et al. Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis. Nat Med, 2013,19(9):1157-1160.
[37]	Zhang D, Lu Y, Liu K , et al. Identification of less lipophilic riminophenazine derivatives for the treatment of drug-resistant tuberculosis. J Med Chem, 2012,55(19):8409-8417.

药物名称	靶点		作用机制		分类			临床阶段	临床试验编号
德拉马尼 (OPC-67683)	靶点尚未明确		抑制细胞壁生成和细胞呼吸		硝基咪唑			临床Ⅲ期	NCT01424670
普瑞马尼 (PA-824)	靶点尚未明确		抑制细胞壁生成和细胞呼吸		硝基咪唑			临床Ⅲ期	NCT02342886
BTZ043	DprE1		抑制细胞壁合成		苯并噻嗪酮			临床Ⅰ期	NCT04044001
PBTZ169 (macozinone)	DprE1		抑制细胞壁合成		苯并噻嗪酮			临床Ⅰ期	NCT04150224
SQ109	MmpL3		抑制细胞壁合成		二胺类衍生物			临床Ⅱ期	NCT01785186
OPC-167832	DprE1		抑制细胞壁合成		氟喹诺酮			临床Ⅰ期	NCT03678688
TBA-7371	DprE1		抑制细胞壁合成		氮杂吲哚			临床Ⅰ期	NCT03199339
PNU-100480 (sutezolid)	23S rRNA		抑制蛋白质合成		恶唑烷酮			临床Ⅱ期	NCT03959566
LCB01-0371 (delpazolid)	23S rRNA		抑制蛋白质合成		恶唑烷酮			临床Ⅱ期	NCT02836483
GSK3036656	LeuRS		抑制蛋白质合成		氧杂硼杂环戊烯			临床Ⅱ期	NCT03557281
贝达喹啉 (TMC207)	atpE		抑制ATP合成酶		二芳基喹啉			临床Ⅲ期	NCT00910871
Q203 (telacebec)	qcrB		抑制细胞呼吸		咪唑并吡啶			临床Ⅱ期	NCT03563599
药物名称		靶点		作用机制		分类	化学结构			临床阶段	临床试验编号
TBI-166		靶点尚未明确		抑制电子链传递和细胞呼吸		氯苯吩嗪				临床Ⅰ期	暂无数据