Research progress on drug resistance of Mycobacterium tuberculosis to Delamanid and its molecular mechanism

doi:10.19983/j.issn.2096-8493.20210131

Abstract

Abstract:

Tuberculosis (TB) is one of the major causes of death for infectious diseases. The emergence of drug-resistant TB increased the difficulty for TB prevention and control. As a new anti-tuberculosis drug, Delamanid performs its bactericidal action by inhibiting the synthesis of mycolic acid of Mycobacterium tuberculosis cell wall, and has good tolerance and safety. However, within a year of clinical application, drug resistance against Delamanid has already been observed. This paper reviewed the clinical application, antibacterial mechanism, drug susceptibility test technologies, epidemiological investigation and molecular mechanism of drug resistance of Delamanid,in order to promote clinical understanding of Delamanid and provide more reference for rational treatment of drug-resistant tuberculosis patients.

Key words: Mycobacterium, tuberculosis, Delamanid, Microbial sensitivity test, Drug resistance, Gene

CLC Number:

R378.911

ZHOU Ming, LIU Huang-rong, TANG Liu-sheng, LIU Sang, LIU Ai-mei. Research progress on drug resistance of Mycobacterium tuberculosis to Delamanid and its molecular mechanism[J]. Journal of Tuberculosis and Lung Disease , 2022, 3(2): 153-157. doi: 10.19983/j.issn.2096-8493.20210131

Figures/Tables 1

国家,发表年份	药物敏感性试验方法		MIC(mg/L)		菌株类型		菌株数		突变基因		突变类型			参考文献
韩国,2018年	微量肉汤稀释法(BMD)		0.32		XDR-TB/MDR-TB菌株		41		ddn		Gly81Ser,Gly81Asp			[28]
	微量肉汤稀释法(BMD)		≤0.0125		敏感菌株		379		ddn,fbiA		Gly81Ser,Leu113Leu等
瑞士,2020年	微量肉汤稀释法(BMD)		0.015~0.03		未经治疗结核病患者菌株		9		fgd1		Lys270Met,T960C			[29]
	微量肉汤稀释法(BMD)		>8		未经治疗死亡的结核病患者菌株		1		ddn,fgd1		Tyr29del,T960C
意大利,2016年	刃天青微量稀释法(REMA)		0.32		XDR-TB菌株		1		fbiA		Lys-250 STOP			[22]
	刃天青微量稀释法(REMA)		0.125		敏感菌株		108		fbiA,fbiB,fbiC, ddn,fgd1		Ary-72Trp, Glu-83-Asp等
意大利,2020年	刃天青微量稀释法(REMA)		0.12~4		TB遗传变异株		74		fbiA,fbiB,fbiC, ddn,fgd1		I208V,Q58Stop, D224N等			[24]
国家,发表年份		药物敏感性试验方法		MIC(mg/L)		菌株类型		菌株数		突变基因		突变类型	参考文献
德国,2019年		刃天青微量稀释法(REMA)		0.25		获得性 delamanid 耐药患者菌株		1		ddn		G53D	[25]
德国,2016年		刃天青微量稀释法(REMA)		≥2.0		MDR-TB菌株		1		fbiA		D49Y,R175H	[39]
		刃天青微量稀释法(REMA)		≤0.016		敏感菌株		1		fbiA		R175H
中国,2017		7H10/7H11琼脂比例法 (APM)		≤0.031		XDR-TB菌株		86		fbiC		val318lle	[27]
		7H10/7H11琼脂比例法 (APM)		一株MIC>0.5,一株MIC>32		XDR-TB菌株		4
美国,2016年		7H10/7H11琼脂比例法 (APM)		0.001~0.05之间, 1株>1,.1株>8		MTB临床分离株		460		-		-	[26]
意大利,2016年		7H10/7H11琼脂比例法 (APM)		0.16		MDR-TB菌株		3		ddn		Trp-88→stop	[22]
		7H10/7H11琼脂比例法 (APM)		0.32		XDR-TB菌株		1		fbiA		Lys-250 STOP
		7H10/7H11琼脂比例法 (APM)		0.125		敏感菌株		108		fbiA,fbiB,fbiC, ddn,fgd1		Ary-72Trp, Glu-83-Asp等
瑞士,2015年		MGIT 960液体药敏试验		0.01		MDR-TB菌株		1		fbiA		D49T	[35]
瑞士,2015年		MGIT 960液体药敏试验		0.005~0.04		敏感菌株		12		-		-	[21]
		MGIT 960液体药敏试验		0.32		耐药菌株		3		-		-
意大利,2016年		MGIT 960液体药敏试验		0.16		MDR-TB菌株		3		ddn		Trp-88→stop	[22]
		MGIT 960液体药敏试验		0.125		敏感菌株		108		fbiA,fbiB,fbiC, ddn,fgd1		Ary-72Trp, Glu-83-Asp等
意大利,2018年		微量滴度平板试验UKMYC5		0.06		外部质量评估(EQA)菌株		19		-		-	[30]

References 40

[1]	刘国标, 谭守勇, 林晓珊, 等. 200例初治菌阳肺结核患者一线抗结核药物治疗后不良反应分析. 结核与肺部疾病杂志, 2015, 4(4):228-232. doi: 10.3969/j.issn.2096-8493.2015.04.005. doi: 10.3969/j.issn.2096-8493.2015.04.005
[2]	陆伟, 傅衍勇. 我国耐药结核病控制的现状与展望. 结核与肺部疾病杂志, 2016, 5(4):259-261. doi: 10.3969/j.issn.2096-8493.2016.04.002. doi: 10.3969/j.issn.2096-8493.2016.04.002
[3]	Ryan NJ, Lo JH. Delamanid: First global approval. Drugs, 2014, 74(9):1041-1045. doi: 10.1007/s40265-014-0241-5. doi: 10.1007/s40265-014-0241-5 URL
[4]	Bahuguna A, Rawat DS. An overview of new antitubercular drugs, drug candidates, and their targets. Med Res Rev, 2019, 40(1):263-292. doi: 10.1002/med.21602. doi: 10.1002/med.21602 URL
[5]	Liu Y, Matsumoto M, Ishida H, et al. Delamanid: From discovery to its use for pulmonary multidrug-resistant tuberculosis (MDR-TB). Curr Top Microbiol, 2018, 111:20-30. doi: 10.1016/j.tube.2018.04.008. doi: 10.1016/j.tube.2018.04.008
[6]	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. PLoS Med, 2006, 3(11):e466. doi: 10.1371/journal.pmed.0030466. doi: 10.1371/journal.pmed.0030466 URL
[7]	Skripconoka V, Danilovits M, Pehme L, et al. Delamanid improves outcomes and reduces mortality in multidrug-resis-tant tuberculosis. Eur Respir J, 2012, 41(6):1393-1400. doi: 10.1183/09031936.00125812. doi: 10.1183/09031936.00125812 URL
[8]	Wells CD, Gupta R, Hittel N, et al. Long-term mortality assessment of multidrug-resistant tuberculosis patients treated with delamanid. Eur Respir J, 2015, 45(5):1498-1501. doi: 10.1183/09031936.00176314. doi: 10.1183/09031936.00176314 URL
[9]	Blair HA, Scott LJ. Delamanid: A review of its use in patients with multidrug-resistant tuberculosis. Drugs, 2014, 75(1):91-100. doi: 10.1007/s40265-014-0331-4. doi: 10.1007/s40265-014-0331-4 URL
[10]	Kuksa L, Barkane L, Hittel N, et al. Final treatment outcomes of multidrug- and extensively drug-resistant tuberculosis patients in latvia receiving delamanid-containing regimens. Eur Respir J, 2017, 50(5):1701105. doi: 10.1183/13993003.01105-2017. doi: 10.1183/13993003.01105-2017 URL
[11]	Li Y, Sun F, Zhang W. Bedaquiline and delamanid in the treatment of multidrug-resistant tuberculosis: Promising but challenging. Drug Dev Res, 2018, 80(1):98-105. doi: 10.1002/ddr.21498. doi: 10.1002/ddr.21498 URL
[12]	Pontali E, Sotgiu G, Tiberi S, et al. Combined treatment of drug-resistant tuberculosis with bedaquiline and delamanid: a systematic review. Eur Respir J, 2018, 52(1):1800934. doi: 10.1183/13993003.00934-2018. doi: 10.1183/13993003.00934-2018 URL
[13]	Diacon A, Dawson R, Hanekom M, et al. Early bactericidal activity of delamanid (OPC-67683) in smear-positive pulmonary tuberculosis patients. Int J Tuberc Lung Dis, 2011, 15(7):949-954. doi: 10.5588/ijtld.10.0616. doi: 10.5588/ijtld.10.0616 URL
[14]	von Groote-Bidlingmaier F, Patientia R, Sanchez E, et al. Efficacy and safety of delamanid in combination with an optimised background regimen for treatment of multidrug-resistant tuberculosis: a multicentre, randomised, double-blind, placebo-controlled, parallel group phase 3 trial. Lancet Respir Med, 2019, 7(3):249-259. doi: 10.1016/s2213-2600(18)30426-0. doi: 10.1016/S2213-2600(18)30426-0 pmid: 30630778
[15]	Xavier AS, Lakshmanan M. Delamanid: A new armor in combating drug-resistant tuberculosis. J Pharmacol Pharmacother, 2014, 5(3):222. doi: 10.4103/0976-500x.136121. doi: 10.4103/0976-500x.136121 URL
[16]	Singh R, Manjunatha U, Boshoff HIM, et al. -824 kills nonreplicating mycobacterium tuberculosis by intracellular NO release. Science, 2008, 322(5906):1392-1395. doi: 10.1126/science.1164571. doi: 10.1126/science.1164571 URL
[17]	Gler MT, Skripconoka V, Sanchez-Garavito E, et al. Delamanid for multidrug-resistant pulmonary tuberculosis. N Engl J Med, 2012, 366(23):2151-2160. doi: 10.1056/nejmoa1112433. doi: 10.1056/nejmoa1112433 URL
[18]	Haver HL, Chua A, Ghode P, et al. Mutations in genes for the F420 biosynthetic pathway and a nitroreductase enzyme are the primary resistance determinants in spontaneous in vitro-selected PA-824-resistant mutants of mycobacterium tuberculosis. Antimicrob Agents Chemother, 2015, 59(9):5316-5323. doi: 10.1128/aac.00308-15. doi: 10.1128/AAC.00308-15 pmid: 26100695
[19]	Fujiwara M, Kawasaki M, Hariguchi N, et al. Mechanisms of resistance to delamanid, a drug for mycobacterium tuberculosis. Curr Top Microbiol, 2018, 108:186-194. doi: 10.1016/j.tube.2017.12.006. doi: 10.1016/j.tube.2017.12.006
[20]	World Health Organization. Technical report on critical concentrations for drug susceptibility testing of medicines used in the treatment of tuberculosis.http://apps.who.int/iris/bitstream/10665/260470/1/WHO-CDS-TB-2018.5-eng.pdf
[21]	Keller PM, Hömke R, Ritter C, et al. Determination of MIC distribution and epidemiological cutoff values for bedaquiline and delamanid in mycobacterium tuberculosis using the MGIT 960 system equipped with TB eXiST. Antimicrob Agents Chemother, 2015, 59(7):4352-4355. doi: 10.1128/aac.00614-15. doi: 10.1128/AAC.00614-15 pmid: 25941226
[22]	Schena E, Nedialkova L, Borroni E, et al. Delamanid susceptibility testing of Mycobacterium tuberculosis using the resazurin microtitre assay and the BACTEC MGIT 960 system. J Antimicrob Chemother, 2016, 71(6):1532-1539. doi: 10.1093/jac/dkw044. doi: 10.1093/jac/dkw044 pmid: 27076101
[23]	Bloemberg GV, Keller PM, Stucki D, et al. Acquired resis-tance to bedaquiline and delamanid in therapy for tuberculosis. N Engl J Med, 2015, 373(20):1986-1988. doi: 10.1056/nejmc1505196. doi: 10.1056/nejmc1505196 URL
[24]	Battaglia S, Spitaleri A, Cabibbe AM, et al. Characterization of genomic variants associated with resistance to bedaquiline and delamanid in naive mycobacterium tuberculosis clinical strains. J Clin Microbiol, 2020, 58(11):e01304-20. doi: 10.1128/jcm.01304-20. doi: 10.1128/jcm.01304-20
[25]	Polsfuss S, Hofmann-Thiel S, Merker M, et al. Emergence of low-level delamanid and bedaquiline resistance during extremely drug-resistant tuberculosis treatment. Clin Infect Dis, 2019, 69(7):1229-1231. doi: 10.1093/cid/ciz074. doi: 10.1093/cid/ciz074 pmid: 30933266
[26]	Stinson K, Kurepina N, Venter A, et al. of delamanid (OPC-67683) against mycobacterium tuberculosis clinical isolates and a proposed critical concentration. Antimicrob Agents Chemother, 2016, 60(6):3316-3322. doi: 10.1128/aac.03014-15. doi: 10.1128/AAC.03014-15 pmid: 26976868
[27]	Pang Y, Zong Z, Huo F, et al. In vitro drug susceptibility of bedaquiline, delamanid, linezolid, clofazimine, moxifloxacin, and gatifloxacin against extensively drug-resistant tuberculosis in beijing, china. Antimicrob Agents Chemother, 2017, 61(10):e00900-17. doi: 10.1128/aac.00900-17. doi: 10.1128/aac.00900-17
[28]	Yang JS, Kim KJ, Choi H, et al. Delamanid, bedaquiline, and linezolid minimum inhibitory concentration distributions and resistance-related gene mutations in multidrug-resistant and extensively drug-resistant tuberculosis in korea. Ann Lab Med, 2018, 38(6):563-568. doi: 10.3343/alm.2018.38.6.563. doi: 10.3343/alm.2018.38.6.563 URL
[29]	Reichmuth ML, Hömke R, Zürcher K, et al. Natural polymorphisms in mycobacterium tuberculosis conferring resistance to delamanid in drug-naive patients. Antimicrob Agents Chemother, 2020, 64(11):e00513-20. doi: 10.1128/aac.00513-20. doi: 10.1128/aac.00513-20
[30]	Rancoita PMV, Cugnata F, Cruz ALG, et al. Validating a 14-drug microtiter plate containing bedaquiline and delamanid for large-scale research susceptibility testing of mycobacterium tuberculosis. Antimicrob Agents Chemother, 2018, 62(9):e00344-18. doi: 10.1128/aac.00344-18. doi: 10.1128/aac.00344-18
[31]	Wen S, Jing W, Zhang T, et al. Comparison of in vitro activity of the nitroimidazoles delamanid and pretomanid against multidrug-resistant and extensively drug-resistant tuberculosis. Eur J Clin Microbiol Infect Dis, 2019, 38(7):1293-1296. doi: 10.1007/s10096-019-03551-w. doi: 10.1007/s10096-019-03551-w URL
[32]	Fujiwara M, Kawasaki M, Hariguchi N, et al. Mechanisms of resistance to delamanid, a drug for mycobacterium tuberculosis. Curr Top Microbiol, 2018, 108:186-194. doi: 10.1016/j.tube.2017.12.006. doi: 10.1016/j.tube.2017.12.006
[33]	Feuerriegel S, Köser CU, Baù D, et al. Impact of fgd1 and ddn diversity in mycobacterium tuberculosis complex on in vitro susceptibility to PA-824. Antimicrob Agents Chemother, 2011, 55(12):5718-5722. doi: 10.1128/aac.05500-11. doi: 10.1128/AAC.05500-11 pmid: 21930879
[34]	Gurumurthy M, Mukherjee T, Dowd CS, et al. Substrate specificity of the deazaflavin-dependent nitroreductase from mycobacterium tuberculosis responsible for the bioreductive activation of bicyclic nitroimidazoles. Barry CE 3rd, Manjunatha UH, 2012, 279(1):113-125. doi: 10.1111/j.1742-4658.2011.08404.x. doi: 10.1111/j.1742-4658.2011.08404.x
[35]	Bloemberg GV, Keller PM, Stucki D, et al. Acquired resis-tance to bedaquiline and delamanid in therapy for tuberculosis. N Engl J Med, 2015, 373(20):1986-1988. doi: 10.1056/nejmc1505196. doi: 10.1056/nejmc1505196 URL
[36]	Forouhar F, Abashidze M, Xu H, et al. Molecular insights into the biosynthesis of the F420 coenzyme. J Biol Chem, 2008, 283(17):11832-11840. doi: 10.1074/jbc.m710352200. doi: 10.1074/jbc.M710352200 pmid: 18252724
[37]	Rehan AM, Bashiri G, Paterson NG, et al. Cloning, expression, purification, crystallization and preliminary x-ray studies of the c-terminal domain of rv3262 (FbiB) from Mycobacterium tuberculosis. Acta Cryst, 2011, 67(10):1274-1277. doi: 10.1107/s1744309111028958. doi: 10.1107/s1744309111028958
[38]	Bashiri G, Rehan AM, Sreebhavan S, et al. Elongation of the poly-γ-glutamate tail of F420 requires both domains of the F420:-glutamyl ligase (FbiB) of mycobacterium tuberculosis. J Biol Chem, 2016, 291(13):6882-6894. doi: 10.1074/jbc.m115.689026. doi: 10.1074/jbc.M115.689026 pmid: 26861878
[39]	Hoffmann H, Kohl TA, Hofmann-Thiel S, et al. Delamanid and bedaquiline resistance in Mycobacterium tuberculosis Ancestral beijing genotype causing extensively drug-resistant tuberculosis in a tibetan refugee. Am J Resp Crit Care, 2016, 193(3):337-340. doi: 10.1164/rccm.201502-0372le. doi: 10.1164/rccm.201502-0372LE pmid: 26829425
[40]	Ramirez LMN, Vargas KQ, Diaz G. Whole genome sequencing for the analysis of drug resistant strains of mycobacterium tuberculosis: A systematic review for bedaquiline and delamanid. Antibiotics, 2020, 9(3):133. doi: 10.3390/antibiotics9030133. doi: 10.3390/antibiotics9030133 URL