抗结核药物的研究进展

韦媛媛; 杨帆; 汤杰; 于丽芳

doi:10.11665/j.issn.1000-5048.20200215

抗结核药物的研究进展

华东师范大学化学与分子工程学院，上海分子治疗与新药创制工程技术研究中心

基金项目: 国家自然科学基金资助项目(No.21778019)

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出版历程
- 刊出日期: 2020-04-24

Advances in the research of anti-tuberculosis drugs

摘要

摘要: 随着结核病耐药频率不断升高，结核病治疗面临严峻的挑战，因此，研发新型抗结核药物显得尤为重要。在过去十年中，抗结核药物的研发取得了重要进展。本文将对近年来被批准用于临床和正在进行临床试验的新化学实体按靶点进行分类，并综述其作用机制、体内外药理活性、药代动力学性质以及临床研究结果。对抗结核药物的研发进行了展望，以期对结核病药物研发提供参考。
- 抗结核药物 /
- 新化学实体 /
- 作用机制 /
- 临床研究 /
- 进展
Abstract: Tuberculosis(TB)treatment is currently falling into a gigantic dilemma-particularly with the increased frequentcy TB resistance, so the development of new anti-tuberculosis drugs is imperative and has received extensive attention. In the past decade, significant progress has been made in this field. Bedaquiline, delamanid and pretomanid have been approved for the clinical use. In addition, many other drugs and combination protocols are undergoing clinical trials. This review focuses on the new chemical entities for TB treatments from multiple perspectives, including the mechanisms of action, in vitro and in vivo pharmacological activities, pharmacokinetic properties and clinical results. Anti-tuberculosis drug research is prospected to provide a reference for drug deve-lopment.
- anti-tuberculosis drugs /
- new chemical entity /
- mechanism of action /
- clinical research /
- advances

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参考文献(48)

[1]	Geneva: World Health Organization. Global tuberculosisreport 2018[EB/OL].(2018-09-18)[2019-09-11] .https://www.who.int/tb/publications/global_report/en/.
[2]	Zumla A,Nahid P,Cole ST.Advances in the development of new tuberculosis drugs and treatment regimens[J].Nat Rev Drug Discov,2013,12(5):388-404.
[3]	Falzon D,Jaramillo E,Schunemann HJ,et al.WHO guidelines for the programmatic management of drug-resistant tuberculosis:2011 update[J].Eur Respir J,2011,38(3):516-528.
[4]	Brennan PJ.Structure,function,and biogenesis of the cell wall of Mycobacterium tuberculosis[J].Tuberculosis,2003,83(1/2/3):91-97.
[5]	Favrot L,Ronning DR.Targeting the mycobacterial envelope for tuberculosis drug development[J].Expert Rev Anti Infect Ther,2012,10(9):1023-1036.
[6]	Horsburgh CR,D.M,Barry CE,et al.Treatment of tuberculosis[J].N Engl J Med,2015,373(22):2149-2160.
[7]	Matsumoto M,Hashizume H,Tomishige T,et al.OPC-67683,a nitro-dihydro-imidazooxazole derivative with promising action against tuberculosis in vitro and in mice[J].PLoS Med,2006,3(11):2131-2144.
[8]	Fujiwara M, Kawasaki M, Hariguchi N, et al. Mechanisms of resistance to delamanid,a drug for Mycobacterium tuberculosis[J].Tuberculosis,2018,108:186-194.
[9]	Gler MT,Skripconoka V,Sanchez-Garavito E,et al.Delamanid for multidrug-resistant pulmonary tuberculosis[J].N Engl J Med,2012,366(23):2151-2160.
[10]	Liu Y,Matsumoto M,Ishida H,et al.Delamanid:from discovery to its use for pulmonary multidrug-resistant tuberculosis(MDR-TB)[J].Tuberculosis,2018,111:20-30.
[11]	Stover CK,Warrener P,Vandevanter DR,et al.A small-moleculenitroimidazopyran drug candidate for the treatment of tuberculosis[J].Nature,2000,405(6789):962-966.
[12]	Singh R,Manjunatha U,Helena IMB,et al.PA-824 kills nonreplicating Mycobacterium tuberculosis by intracellular NO release[J].Science,2008,322(5906):1392-1395.
[13]	Lenaerts AJ,Veronica G,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[J].Antimicrob Agents Chemother,2005,49(6):2294-2301.
[14]	Sandeep T, Nuermberger E, Yoshimatsu T, et al. Bactericidal activity of the nitroimidazopyran PA-824 in a murine model of tuberculosis[J].Antimicrob Agents Chemother,2005,49(6):2289-2293.
[15]	Diacon AH, Rodney D, Florian GB, et al. 14-day bactericidal activity of PA-824,bedaquiline,pyrazinamide,and moxifloxacin combinations:a randomised trial[J].Lancet,2012,380(9846):986-993.
[16]	Nuermberger E,Tyagi S,Tasneen R,et al.Powerful bactericidal and sterilizing activity of a regimen containing PA-824,moxifloxacin,and pyrazinamide in a murine model of tuberculosis[J].Antimicrob Agents Chemother,2008,52(4):1522-1524.
[17]	Nuermberger E,Rosenthal I,Tyagi S,et al.Combination chemotherapy with the nitroimidazopyran PA-824 and first-line drugs in a murine model of tuberculosis[J].Antimicrob Agents Chemother,2006,50(8):2621-2625.
[18]	Tasneen R, Tyagi S, Williams K, et al. Enhanced bactericidal activity of rifampin and/or pyrazinamide when combined with PA-824 in a murine model of tuberculosis[J].Antimicrob Agents Chemother,2008,52(10):3664-3668.
[19]	Sacksteder KA,Protopopova M,Barry CE,et al.Discovery and development of SQ109:a new antitubercular drug with a novel mechanism of action[J].Future Microbiol,2012,7(7):823-837.
[20]	Chen P.Synergistic interactions of SQ109,a new ethylene diamine,with front-line antitubercular drugs in vitro[J].J Antimicrob Chemoth,2006,58(2):332-337.
[21]	Reddy VM, Einck L, Andries K,et al. In vitro interactions between new antitubercular drug candidates SQ109 and TMC207[J].Antimicrob Agents Chemother,2010,54(7):2840-2846.
[22]	Reddy VM,Dubuisson T,Einck L,et al.SQ109 and PNU-100480 interact to kill Mycobacterium tuberculosis in vitro[J].J Antimicrob Chemoth,2012,67(5):1163-1166.
[23]	Piton J,Vocat A,Lupien A,et al.Structure-based drug design and characterization of sulfonyl-piperazine benzothiazinone inhibitors of DprE1 from Mycobacterium tuberculosis[J].Antimicrob Agents Chemother,2018,62(10):e00681-18.
[24]	Brecik M,Centárová I,Mukherjee R,et al.DprE1 is a vulnerable tuberculosis drug target due to its cell wall localization[J].ACS Chem Biol,2015,10(7):1631-1636.
[25]	Makarov V,Manina G,Mikusova K,et al.Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis[J].Science,2009,324(5928):801-804.
[26]	Lechartier B,Hartkoorn RC,Cole ST.In vitro combination studies of benzothiazinone lead compound BTZ043 against Mycobacterium tuberculosis[J].Antimicrob Agents Chemother,2012,56(11):5790-5793.
[27]	Makarov V,Lechartier B,Zhang M,et al.Towards a new combination therapy for tuberculosis with next generation benzothiazinones[J].Embo Mol Med,2014,6(3):372-383.
[28]	Makarov V,Neres J,Hartkoorn RC,et al.The 8-pyrrole-benzothiazinones are noncovalent inhibitors of DprE1 from Mycobacterium tuberculosis[J].Antimicrob Agents Chemother,2015,59(8):4446-4452.
[29]	Lechartier B,Cole ST.Mode of action of clofazimine and combination therapy with benzothiazinones against Mycobacterium tuberculosis[J].Antimicrob Agents Chemother,2015,59(8):4457-4463.
[30]	Lupien A,Vocat A,Foo CS,et al.Optimized background regimen for treatment of active tuberculosis with the next-generation benzothiazinone Macozinone(PBTZ169)[J].Antimicrob Agents Chemother,2018,62(11):e00840-18.
[31]	Working Group on New TB Drugs[EB/OL].[2019-09-11] .https://www.newtbdrugs.org/pipeline/clinical.
[32]	Chatterji M,Shandil R,Manjunatha MR,et al.1,4-azaindole,a potential drug candidate for treatment of tuberculosis[J].Antimicrob Agents Chemother,2014,58(9):5325-5331.
[33]	Lamprecht DA,Finin PM,Rahman MA,et al.Turning the respi-ratory flexibility of Mycobacterium tuberculosis against itself[J].Nat Commun,2016,7(1):12393.
[34]	Kalia NP,Hasenoehrl EJ,Ab Rahman NB,et al.Exploiting the synthetic lethality between terminal respiratory oxidases to kill Mycobacterium tuberculosis and clear host infection[J].PNAS,2017,114(28):7426-7431.
[35]	Guillemont J,Meyer C,Poncelet A,et al.Diarylquinolines,synthesis pathways and quantitative structure-activity relationship studies leading to the discovery of TMC207[J].Future Med Chem,2011,3(11):1345-1360.
[36]	Ahmad N,Ahuja SD,Akkerman OW,et al.Treatment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis:an individual patient data meta-analysis[J].Lancet,2018,392(10150):821-834.
[37]	Abrahams KA,Cox JA,Spivey VL,et al.Identification of novel imidazo[1,2-a]pyridine inhibitors targeting M.tuberculosis QcrB[J].PLoS One,2012,7(12):e52951.
[38]	Pethe K,Bifani P,Jang J,et al.Discovery of Q203,a potent clinical candidate for the treatment of tuberculosis[J].Nat Med,2013,19(9):1157-1160.
[39]	Barbachyn MR,Hutchinson DK,Brickner SJ,et al.Identification of a novel oxazolidinone(U-100480)with potent antimycobacterial activity[J].J Med Chem,1996,39(3):680-685.
[40]	Williams KN,Stover CK,Zhu T,et al.Promising antituberculosis activity of the oxazolidinone PNU-100480 relative to that of linezolid in a murine model[J].Antimicrob Agents Chemother,2009,53(4):1314-1319.
[41]	Williams KN,Brickner SJ,Stover CK,et al.Addition of PNU-100480 to first-line drugs shortens the time needed to cure murine tuberculosis[J].Am J Resp Crit Care,2009,180(4):371-376.
[42]	Wallis RS,Jakubiec WM,Kumar V,et al.Pharmacokinetics and whole-blood bactericidal activity against Mycobacterium tuberculosis of single doses of PNU-100480 in healthy volunteers[J].J Infect Dis,2010,202(5):745-751.
[43]	Wallis RS,Jakubiec W,Kumar V,et al.Biomarker-assisted dose selection for safety and efficacy in early development of PNU-100480 for tuberculosis[J].Antimicrob Agents Chemother,2011,55(2):567-574.
[44]	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].J Med Chem,2017,60(19):8011-8026.
[45]	Tenero D,Derimanov G,Carlton A,et al.First-time-in-human study and prediction of early bactericidal activity for GSK3036656,a potent leucyl-tRNA synthetase inhibitor for tuberculosis treatment[J].Antimicrob Agents Chemother,2019,63(8):e00240-19.
[46]	Ralph AP,Kenangalem E,Waramori G,et al.High morbidity during treatment and residual pulmonary disability in pulmonary tuberculosis:under-recognised phenomena[J].PLoS One,2013,8(11):e80302.
[47]	Willcox PA,Ferguson AD.Chronic obstructive airways disease following treated pulmonary tuberculosis[J].Resp Med,1989,83(3):195-198.
[48]	Wallis RS,Maeurer M,Mwaba P,et al.Tuberculosis—advances in development of new drugs,treatment regimens,host-directed therapies,and biomarkers[J].Lancet Infect Dis,2016,16(4):e34-e46.