首页 中华结核和呼吸杂志 2020年43卷1期 耐药结核病治疗药物研究进展
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耐药结核病治疗药物研究进展
时翠林 
牛广豪
王霞芳 
唐神结
作者及单位信息
·
DOI： 10.3760/cma.j.issn.1001-0939.2020.01.013
Progress in research on drug-resistant tuberculosis drugs
Shi Cuilin
Niu Guanghao
Wang Xiafang
Tang Shenjie
Authors Info & Affiliations
Shi Cuilin
Niu Guanghao
Wang Xiafang
Tang Shenjie
·
DOI： 10.3760/cma.j.issn.1001-0939.2020.01.013
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摘要
目前结核病仍然是全球十大死因之一，全球耐药结核病的疫情不容乐观。由于抗结核新药的匮乏，耐药结核病治疗非常困难，治疗时间长，成功率低，因此新型抗结核药物的研发非常迫切。近期除了已被世界卫生组织推荐的治疗耐多药肺结核的新药如利奈唑胺、贝达喹啉及德拉马尼外，还有针对结核分枝杆菌的约17种新化合物正处于不同的临床试验阶段。本文将耐药结核病治疗药物研究进展综述如下。
引用本文
时翠林,牛广豪,王霞芳,等. 耐药结核病治疗药物研究进展[J]. 中华结核和呼吸杂志,2020,43(1)：58-63.
DOI:10.3760/cma.j.issn.1001-0939.2020.01.013PERMISSIONS
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结核病仍然是全球十大死因之一，2018年世界卫生组织报告全球结核病估算新发病例约1 010万例，死亡病例约160万例。耐药结核病的全球形式不容乐观，2017年全球估计新发利福平耐药结核病（rifampicin-resistant tuberculosis, RR-TB）患者约55.8万例，其中82%为耐多药结核病（multi drug-resistant tuberculosis, MDR-TB），其中8.5%为广泛耐药结核病（extensively drug-resistant tuberculosis, XDR-TB）
[
1
]。但在现有抗结核药物的条件下，MDR-TB和XDR-TB治疗时间长且非常困难，成功率低于50%
[
2
]，因此抗耐药结核新药的研发势在必行。近期世界卫生组织建议治疗耐多药结核病的新药除利奈唑胺、贝达喹啉及德拉马尼外，还有约17种针对MTB的新化合物正处于不同的试验阶段。本文就目前临床前期和临床Ⅰ、Ⅱ期试验阶段以及已上市的抗结核新药综述如下，供国内同道借鉴。
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参考文献
[1]
World Health Organization. Global tuberculosis report 2018. WHO/CDS/TB/2018.20[M]. Geneva:World Health Organization, 2018.
[2]
World Health Organization. Rapid communication: key changes to treatment of multidrug-and rifampicin-resistant tuberculosis (MDR/RR-TB). WHO/CDS/TB/2018.18[M]. Geneva:World Health Organization, 2018.
[3]
Mdluli K , Cooper C , Yang T ,et al. TBI-223: a Safer Oxazolidinone in Pre-Clinical Development for Tuberculosis[EB/OL]. [ 2018-07-12]. http://www.abstractsonline.com/pp8/#!/4358/presentation/6174.
[4]
Sutherland HS , Tong AST , Choi PJ ,et al. Structure-activity relationships for analogs of the tuberculosis drug bedaquiline with the naphthalene unit replaced by bicyclic heterocycles[J]. Bioorg Med Chem, 2018,26(8):1797-1809. DOI:
10.1016/j.bmc.2018.02.026
.
[5]
Choi PJ , Sutherland HS , Tong AS ,et al. Synthesis and evaluation of analogues of the tuberculosis drug bedaquiline containing heterocyclic B-ring units[J]. Bioorg Med Chem Lett, 2017,27(23):5190-5196. DOI:
10.1016/j.bmcl.2017.10.042
.
[6]
Robertson GT , Scherman MS , Bruhn DF ,et al. Spectinamides are effective partner agents for the treatment of tuberculosis in multiple mouse infection models[J]. J Antimicrob Chemother, 2017,72(3):770-777. DOI:
10.1093/jac/dkw467
.
[7]
Madhura DB , Liu J , Meibohm B ,et al. Phase Ⅱ Metabolic Pathways of Spectinamide Antitubercular Agents: a Comparative Study of the Reactivity of 4-Substituted Pyridines to Glutathione Conjugation[J]. Med Chemcomm, 2016,7(1):114-117. DOI:
10.1039/C5MD00349K
.
[8]
Working Group on New TB Drugs. GlaxoSmithKline TB Drug Accelerator:GSK-286.[EB/OL].[ 2018-07-27]. https://www.newtbdrugs.org/pipeline/compound/gsk-286.
[9]
Rock FL , Mao W , Yaremchuk A ,et al. An antifungal agent inhibits an aminoacyl-tRNAsynthetase by trapping tRNA in the editing site[J]. Science, 2007,316(5832):1759-1761. DOI:
10.1126/science.1142189
.
[10]
Li X , Hernandez V , Rock FL ,et al. Discovery of a Potent and Specific M. tuberculosis Leucyl-tRNASynthetase 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. DOI:
10.1021/acs.jmedchem.7b00631
.
[11]
Palencia A , Li X , Bu W ,et al. Discovery of Novel Oral Protein Synthesis Inhibitors of Mycobacterium tuberculosis That Target Leucyl-tRNASynthetase[J]. Antimicrob Agents Chemother, 2016,60(10):6271-6280. DOI:
10.1128/AAC.01339-16
.
[12]
Makarov V , Manina G , Mikusova K ,et al. Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinansynthesis[J]. Science, 2009,324(5928):801-804. DOI:
10.1126/science.1171583
.
[13]
Kloss F , Krchnak V , Krchnakova A ,et al. In Vivo Dearomatization of the Potent Antituberculosis Agent BTZ043 via Meisenheimer Complex Formation[J]. Angew Chem Int Ed Engl, 2017,56(8):2187-2191. DOI:
10.1002/anie.201609737
.
[14]
Working Group on New TB Drugs. TBA-7371.[EB/OL].[ 2018-08-02]. https://www.newtbdrugs.org/pipeline/compound/tba-7371.
[15]
A Phase 1 Study to Evaluate Safety, Tolerability, PK, and PK Interactions of TBA-7371.[EB/OL].[ 2018-08-02]. https://clinicaltrials.gov/ct2/show/NCT03199339.
[16]
Otsuka Awarded Grant to Advance Development of Novel Anti-Tuberculosis Compound OPC-167832 with Delamanid.[EB/OL].[ 2018-08-02]. https://www.businesswire.com/news/home/20180129005073/en/Otsuka-Awarded-Grant-Advance-Development-Anti-Tuberculosis-Compound.
[17]
Hafkin J . Updates in the Development of Delamanid, OPC167832, and Otsuka′s LAM Biomarker.[EB/OL].[ 2018-07-23]. http://www.cptrinitiative.org/wp-content/uploads/2017/05/Jeffrey_Hafkin_CPTR2017_JH.pdf.
[18]
Lu Y , Zheng M , Wang B ,et al. Clofazimine analogs with efficacy against experimental tuberculosis and reduced potential for accumulation[J]. Antimicrob Agents Chemother, 2011,55(11):5185-5193. DOI:
10.1128/AAC.00699-11
.
[19]
Zhang D , Liu Y , Zhang C ,et al. Synthesis and biological evaluation of novel 2-methoxypyridylamino-substituted riminophenazine derivatives as antituberculosis agents[J]. Molecules, 2014,19(4):4380-4394. DOI:
10.3390/molecules19044380
.
[20]
Zhang D , Lu Y , Liu K ,et al. Identification of less lipophilic riminophenazine derivatives for the treatment of drug-resistant tuberculosis[J]. J Med Chem, 2012,55(19):8409-8417. DOI:
10.3390/molecules19044380
.
[21]
Harbut MB , Vilcheze C , Luo X ,et al. Auranofin exerts broad-spectrum bactericidal activities by targeting thiol-redox homeostasis[J]. Proc Natl AcadSci U S A, 2015,112(14):4453-4458. DOI:
10.1073/pnas.1504022112
.
[22]
Leach KL , Swaney SM , Colca JR ,et al. The site of action of oxazolidinone antibiotics in living bacteria and in human mitochondria[J]. Mol Cell, 2007,26(3):393-402. DOI:
10.1016/j.molcel.2007.04.005
.
[23]
Kim TS , Choe JH , Kim YJ ,et al. Activity of LCB01-0371, a Novel Oxazolidinone, against Mycobacterium abscessus[J]. Antimicrob Agents Chemother, 2017,61(9):7-12. DOI:
10.1128/AAC.02752-16
.
[24]
Jeong JW , Jung SJ , Lee HH ,et al. In Vitro and In Vivo Activities of LCB01-0371, a New Oxazolidinone[J]. Antimicrob Agents Chemother, 2010,54(12):5359-5362. DOI:
10.1128/AAC.00723-10
.
[25]
Shigyo K , Ocheretina O , Merveille YM ,et al. Efficacy of nitazoxanide against clinical isolates of Mycobacterium tuberculosis[J]. Antimicrob Agents Chemother, 2013,57(6):2834-2837. DOI:
10.1128/AAC.02542-12
.
[26]
de Carvalho LP , Lin G , Jiang X ,et al. Nitazoxanide kills replicating and nonreplicating Mycobacterium tuberculosis and evades resistance[J]. J Med Chem, 2009,52(19):5789-5792. DOI:
10.1021/jm9010719
.
[27]
Harausz EP , Chervenak KA , Good CE ,et al. Activity of nitazoxanide and tizoxanide against Mycobacterium tuberculosis in vitro and in whole blood culture[J]. Tuberculosis (Edinb), 2016,98:92-96. DOI:
10.1016/j.tube.2016.03.002
.
[28]
Wallis RS , Jakubiec W , Mitton-Fry M ,et al. Rapid evaluation in whole blood culture of regimens for XDR-TB containing PNU-100480 (sutezolid), TMC207, PA-824, SQ109, and pyrazinamide[J]. PLoS One, 2012,7(1):e30479. DOI:
10.1371/journal.pone.0030479
.
[29]
Jia L , Tomaszewski JE , Hanrahan C ,et al. Pharmacodynamics and pharmacokinetics of SQ109, a new diamine-based antitubercular drug[J]. Br J Pharmacol, 2005,144(1):80-87. DOI:
10.1038/sj.bjp.0705984
.
[30]
Chen P , Gearhart J , Protopopova M ,et al. Synergistic interactions of SQ109, a new ethylene diamine, with front-line antitubercular drugs in vitro[J]. J Antimicrob Chemother, 2006,58(2):332-337. DOI:
10.1093/jac/dkl227
.
[31]
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. DOI:
10.2217/fmb.12.56
.
[32]
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. DOI:
10.1128/AAC.01182-08
.
[33]
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. DOI:
10.1086/655471
.
[34]
Wallis RS , Dawson R , Friedrich SO ,et al. Mycobactericidal activity of sutezolid (PNU-100480) in sputum (EBA) and blood (WBA) of patients with pulmonary tuberculosis[J]. PLoS One, 2014,9(4):e94462. DOI:
10.1371/journal.pone.0094462
.
[35]
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. DOI:
10.1128/AAC.01179-10
.
[36]
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]. Proc Natl AcadSci U S A, 2017,114(28):7426-7431. DOI:
10.1073/pnas.1706139114
.
[37]
Jang J , Kim R , Woo M ,et al. Efflux Attenuates the Antibacterial Activity of Q203 in Mycobacterium tuberculosis[J]. Antimicrob Agents Chemother, 2017,61(7). DOI:
10.1128/AAC.02637-16
.
[38]
Kang S , Kim RY , Seo MJ ,et al. Lead optimization of a novel series of imidazo[1,2-a]pyridine amides leading to aclinical candidate (Q203) as a multi-and extensively-drug-resistant anti-tuberculosis agent[J]. J Med Chem, 2014,57(12):5293-5305. DOI:
10.1021/jm5003606
.
[39]
Lv K , You X , Wang B ,et al. Identification of better pharmacokinetic benzothiazinone derivatives as new antitubercularagents[J]. ACS Med Chem Lett, 2017,8(6):636-641. DOI:
10.1021/acsmedchemlett.7b00106
.
[40]
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. DOI:
10.1002/emmm
.
[41]
中华医学会结核病学分会，抗结核药物超说明书用法专家共识编写组. 抗结核药物超说明书用法专家共识[J]. 中华结核和呼吸杂志, 2018,41(6):447-460. DOI:
10.3760/cma.j.issn.1001-0939.2018.06.006
.
[42]
中华医学会结核病学分会，利奈唑胺抗结核治疗专家共识编写组. 利奈唑胺抗结核治疗专家共识[J]. 中华结核和呼吸杂志, 2018,41(1):14-19. DOI:
10.3760/cma.j.issn.1001-0939.2018.01.006
.
[43]
Zhang X , Falagas ME , Vardakas KZ ,et al. Systematic review and meta-analysis of the efficacy safety of therapy with linezolid containing regimens in the treatment of multidrug-resistant and extensively drug-resistant tuberculosis[J]. J Thorac Dis, 2015,7(4):603-615. DOI:
10.3978/j.issn.2072-1439.2015.03.10
.
[44]
Tang S , Yao L , Hao X ,et al. Efficacy, safety and tolerability of linezolid for the treatment of XDR-TB: a study in China[J]. EurRespir J, 2015,45(1):161-170. DOI:
10.1183/09031936.00035114
.
[45]
Fox GJ , Menzies D . A Review of the Evidence for Using Bedaquiline (TMC207) to Treat Multi-Drug Resistant Tuberculosis[J]. Infect Dis therapy, 2013,2(2):123-144. DOI:
10.1007/s40121-013-0009-3
.
[46]
Koul A , Vranckx L , Dhar N ,et al. Delayed bactericidal response of Mycobacterium tuberculosis to bedaquiline involves remodelling of bacterial metabolism[J]. Nat Commun, 2014,5:3369. DOI:
10.1038/ncomms4369
.
[47]
Rouan MC , Lounis N , Gevers T ,et al. Pharmacokinetics and pharmacodynamics of TMC207 and its N-desmethyl metabolite in a murine model of tuberculosis[J]. Antimicrob Agents Chemother, 2012,56(3):1444-1451. DOI:
10.1128/AAC.00720-11
.
[48]
中华医学会结核病学分会，抗结核新药贝达喹啉临床应用专家共识编写组. 抗结核新药贝达喹啉临床应用专家共识[J]. 中华结核和呼吸杂志, 2018,41(6):461-466. DOI:
10.3760/cma.j.issn.1001-0939.2018.06.005
.
[49]
Diacon AH , Dawson R , Hanekom M ,et al. Early bactericidal activity of delamanid (OPC-67683) in smear-positive pulmonary tuberculosis patients[J]. Int J Tuberc Lung D, 2011,15(7):949-954. DOI:
10.5588/ijtld.10.0616
.
[50]
World Health Organization. Companion handbook to the WHO guidelines for the programmatic management of drug-resistant tuberculosis.WHO/HTM/TB/2014.11[M]. Geneva:World Health Orgination, 2014.
[51]
Ferlazzo G , Mohr E , Laxmeshwar C ,etal. Early safety and efficacy of the combination of bedaquiline and delamanid for the treatment of patients with drug-resistant tuberculosis in Armenia, India, and South Africa: a retrospective cohort study[J]. Lancet Infect Dis, 2018,18(5):536-544. DOI:
10.1016/S1473-3099(18)30100-2
.
[52]
Guglielmetti L , Barkane L , Le Dû D ,et al. Safety and efficacy of exposure to bedaquiline-delamanid in multidrug-resistant tuberculosis: a case series from France and Latvia[J]. Eur respir J, 2018,51(3).
10.1183/13993003.02550-2017
. DOI:.
备注信息
A
唐神结，Email：
mocdef.aabnis.piv6011jsgnat
B
王霞芳，Email：
mocdef.3ab61fxgnaw
C
所有作者均声明不存在利益冲突
D
苏州市中西医结合科研基金 (SYSD2016167)
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