Research status of drug resistance of antituberculosis drugs bedaquiline and clofazimine

doi:10.19982/j.issn.1000-6621.20220292

Abstract

Abstract:

The emergence of multidrug-/rifampicin-resistant tuberculosis (MDR/RR-TB) and extensively drug-resistant tuberculosis (XDR-TB) poses a huge threat to tuberculosis (TB) control worldwide. Due to the lack of effective drugs, the success rate for MDR-TB patients was only 59%, and less than 50% for XDR-TB patients. In recent years, the application of the new anti-TB drug bedaquiline (Bdq) and the old drug clofazimine (Cfz) in patients with MDR/RR-TB and XDR-TB can significantly improve the treatment outcomes of patients. Both drugs work by impairing energy metabolism of mycobacterium and are still used in combination by clinicians in clinical care despite cross-resistance. Therefore, in the process of clinical application, attention should be paid not only to the adverse drug reactions, but also to the drug resistance of Bdq and Cfz. The author aims to summarize the mechanisms associated with drug resistance of Bdq and Cfz, the emergence of drug resistance of Bdq and Cfz in clinical treatment, and to discuss how to delay the accumulation and spread of acquired drug resistance of Bdq and Cfz.

Key words: Tuberculosis, Chemistry, pharmaceutical, Drug resistance, Review literature as topic

CLC Number:

R52
S481+.4

Shang Yuanyuan, Nie Wenjuan, Huang Hairong, Chu Naihui. Research status of drug resistance of antituberculosis drugs bedaquiline and clofazimine[J]. Chinese Journal of Antituberculosis, 2023, 45(1): 116-122. doi: 10.19982/j.issn.1000-6621.20220292

Figures/Tables 2

References 64

[1]	World Health Organization.Global tuberculosis report 2020. Geneva: Word Health Organization, 2020.
[2]	World Health Organization. Global tuberculosis report 2021. Geneva: Word Health Organization, 2021.
[3]	World Health Organization. WHO consolidated guidelines on drug-resistant tuberculosis treatment. Geneva: World Health Organization, 2019.
[4]	Nimmo C, Millard J, van Dorp L, et al. Population-level emergence of bedaquiline and clofazimine resistance-associated variants among patients with drug-resistant tuberculosis in southern Africa: a phenotypic and phylogenetic analysis. Lancet Microbe, 2020, 1(4): e165-e174. doi:10.1016/S2666-5247(20)30031-8. doi: 10.1016/S2666-5247(20)30031-8.
[5]	Williams K, Minkowski A, Amoabeng O, et al. Sterilizing activities of novel combinations lacking first- and second-line drugs in a murine model of tuberculosis. Antimicrob Agents Chemother, 2012, 56(6): 3114-3120. doi:10.1128/AAC.00384-12.2. doi: 10.1128/AAC.00384-12 pmid: 22470112
[6]	Nunn AJ, Phillips PPJ, Meredith SK, et al. A Trial of a Shorter Regimen for Rifampin-Resistant Tuberculosis. N Engl J Med, 2019, 380(13): 1201-1213. doi:10.1056/NEJMoa1811867. doi: 10.1056/NEJMoa1811867. URL
[7]	Koul A, Dendouga N, Vergauwen K, et al. Diarylquinolines target subunit c of mycobacterial ATP synthase. Nat Chem Biol, 2007, 3(6): 323-324. doi:10.1038/nchembio884. doi: 10.1038/nchembio884. pmid: 17496888
[8]	Preiss L, Langer JD, Yildiz Ö, et al. Structure of the mycobacterial ATP synthase Fo rotor ring in complex with the anti-TB drug bedaquiline. Sci Adv, 2015, 1(4): e1500106. doi:10.1126/sciadv.1500106. doi: 10.1126/sciadv.1500106. URL
[9]	Borisov SE, Dheda K, Enwerem M, et al. Effectiveness and safety of bedaquiline-containing regimens in the treatment of MDR- and XDR-TB: a multicentre study. Eur Respir J, 2017, 49(5):1700387. doi:10.1183/13993003.00387-2017. doi: 10.1183/13993003.00387-2017. URL
[10]	Schnippel K, Ndjeka N, Maartens G, et al. Effect of bedaquiline on mortality in South African patients with drug-resistant tuberculosis: a retrospective cohort study. Lancet Respir Med, 2018, 6(9): 699-706. doi:10.1016/S2213-2600(18)30235-2. doi: 10.1016/S2213-2600(18)30235-2 pmid: 30001994
[11]	Honeyborne I, Lipman M, Zumla A, et al. The changing treatment landscape for MDR/XDR-TB-Can current clinical trials revolutionise and inform a brave new world? Int J Infect Dis, 2019, 80S: S23-S28. doi:10.1016/j.ijid.2019.02.006. doi: 10.1016/j.ijid.2019.02.006.
[12]	Akkerman O, Aleksa A, Alffenaar JW, et al. Surveillance of adverse events in the treatment of drug-resistant tuberculosis: A global feasibility study. Int J Infect Dis, 2019, 83: 72-76. doi:10.1016/j.ijid.2019.03.036. doi: S1201-9712(19)30165-1 pmid: 30953827
[13]	Van Deun A, Maug AK, Salim MA, et al. Short, highly effective, and inexpensive standardized treatment of multidrug-resistant tuberculosis. Am J Respir Crit Care Med, 2010, 182(5): 684-692. doi:10.1164/rccm.201001-0077OC. doi: 10.1164/rccm.201001-0077OC. URL
[14]	Duan H, Chen X, Li Z, et al. Clofazimine improves clinical outcomes in multidrug-resistant tuberculosis: a randomized controlled trial. Clin Microbiol Infect, 2019, 25(2): 190-195. doi:10.1016/j.cmi.2018.07.012. doi: 10.1016/j.cmi.2018.07.012.
[15]	Tang S, Yao L, Hao X, et al. Clofazimine for the treatment of multidrug-resistant tuberculosis: prospective, multicenter, randomized controlled study in China. Clin Infect Dis, 2015, 60(9): 1361-1367. doi:10.1093/cid/civ027. doi: 10.1093/cid/civ027 pmid: 25605283
[16]	Lamprecht DA, Finin PM, Rahman MA, et al. Turning the respiratory flexibility of Mycobacterium tuberculosis against itself. Nat Commun, 2016, 7: 12393. doi:10.1038/ncomms12393. doi: 10.1038/ncomms12393 pmid: 27506290
[17]	Yano T, Kassovska-Bratinova S, Teh JS, et al. Reduction of clofazimine by mycobacterial type 2 NADH:quinone oxidoreductase: a pathway for the generation of bactericidal levels of reactive oxygen species. J Biol Chem, 2011, 286(12): 10276-10287. doi:10.1074/jbc.M110.200501. doi: 10.1074/jbc.M110.200501 pmid: 21193400
[18]	Mirnejad R, Asadi A, Khoshnood S, et al. Clofazimine: A useful antibiotic for drug-resistant tuberculosis. Biomed Pharmacother, 2018, 105: 1353-1359. doi:10.1016/j.biopha.2018.06.023. doi: S0753-3322(18)32560-5 pmid: 30021373
[19]	Zhang S, Chen J, Cui P, et al. Identification of novel mutations associated with clofazimine resistance in Mycobacterium tuberculosis. J Antimicrob Chemother, 2015, 70(9): 2507-2510. doi:10.1093/jac/dkv150. doi: 10.1093/jac/dkv150 pmid: 26045528
[20]	Zheng H, He W, Jiao W, et al. Molecular characterization of multidrug-resistant tuberculosis against levofloxacin, moxifloxacin, bedaquiline, linezolid, clofazimine, and delamanid in southwest of China. BMC Infect Dis, 2021, 21(1): 330. doi:10.1186/s12879-021-06024-8. doi: 10.1186/s12879-021-06024-8 pmid: 33832459
[21]	Andries K, Verhasselt P, Guillemont J, et al. A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science, 2005, 307(5707): 223-227. doi:10.1126/science.1106753. doi: 10.1126/science.1106753. pmid: 15591164
[22]	Huitric E, Verhasselt P, Koul A, et al. Rates and mechanisms of resistance development in Mycobacterium tuberculosis to a novel diarylquinoline ATP synthase inhibitor. Antimicrob Agents Chemother, 2010, 54(3): 1022-1028. doi:10.1128/AAC.01611-09. doi: 10.1128/AAC.01611-09 pmid: 20038615
[23]	Liu Y, Gao J, Du J, et al. Acquisition of clofazimine resis-tance following bedaquiline treatment for multidrug-resistant tuberculosis. Int J Infect Dis, 2021, 102: 392-396. doi:10.1016/j.ijid.2020.10.081. doi: 10.1016/j.ijid.2020.10.081. URL
[24]	Xu J, Wang B, Hu M, et al. Primary Clofazimine and Beda-quiline Resistance among Isolates from Patients with Multidrug-Resistant Tuberculosis. Antimicrob Agents Chemother, 2017, 61(6): e00239-17. doi:10.1128/AAC.00239-17. doi: 10.1128/AAC.00239-17.
[25]	Ismail NA, Omar SV, Joseph L, et al. Defining Bedaquiline Susceptibility, Resistance, Cross-Resistance and Associated Genetic Determinants: A Retrospective Cohort Study. EBioMedicine, 2018, 28: 136-142. doi:10.1016/j.ebiom.2018.01.005. doi: S2352-3964(18)30005-7 pmid: 29337135
[26]	Zimenkov DV, Nosova EY, Kulagina EV, et al. Examination of bedaquiline- and linezolid-resistant Mycobacterium tuberculosis isolates from the Moscow region. J Antimicrob Chemother, 2017, 72(7): 1901-1906. doi:10.1093/jac/dkx094. doi: 10.1093/jac/dkx094 pmid: 28387862
[27]	Migliori GB, Falzon D, Marks GB, et al. Commemorating World Tuberculosis Day 2022: recent ERJ articles of critical relevance to ending TB and saving lives. Eur Respir J, 2022, 59(3): 2200149. doi:10.1183/13993003.00149-2022. doi: 10.1183/13993003.00149-2022. URL
[28]	Centers for Disease Control and Prevention. Provisional CDC guidelines for the use and safety monitoring of bedaquiline fumarate (Sirturo) for the treatment of multidrug-resistant tuberculosis. MMWR Recomm Rep, 2013, 62(RR-09): 1-12. pmid: 24157696
[29]	Diacon AH, Pym A, Grobusch MP, et al. Multidrug-resistant tuberculosis and culture conversion with bedaquiline. N Engl J Med, 2014, 371(8): 723-732. doi:10.1056/NEJMoa1313865. doi: 10.1056/NEJMoa1313865. URL
[30]	Pontali E, Sotgiu G, D’Ambrosio L, et al. Bedaquiline and multidrug-resistant tuberculosis: a systematic and critical analysis of the evidence. Eur Respir J, 2016, 47(2): 394-402. doi:10.1183/13993003.01891-2015. doi: 10.1183/13993003.01891-2015 pmid: 26828052
[31]	Ghodousi A, Rizvi AH, Baloch AQ, et al. Acquisition of Cross-Resistance to Bedaquiline and Clofazimine following Treatment for Tuberculosis in Pakistan. Antimicrob Agents Chemother, 2019, 63(9): e00915-19. doi:10.1128/AAC.00915-19. doi: 10.1128/AAC.00915-19.
[32]	Hartkoorn RC, Uplekar S, Cole ST. Cross-resistance between clofazimine and bedaquiline through upregulation of MmpL5 in Mycobacterium tuberculosis. Antimicrob Agents Chemother, 2014, 58(5): 2979-2981. doi:10.1128/AAC.00037-14. doi: 10.1128/AAC.00037-14 pmid: 24590481
[33]	Almeida D, Ioerger T, Tyagi S, et al. Mutations in pepQ Confer Low-Level Resistance to Bedaquiline and Clofazimine in Mycobacterium tuberculosis. Antimicrob Agents Chemother, 2016, 60(8): 4590-4599. doi:10.1128/AAC.00753-16. doi: 10.1128/AAC.00753-16 pmid: 27185800
[34]	Loeb LA, Wallace DC, Martin GM. The mitochondrial theory of aging and its relationship to reactive oxygen species damage and somatic mtDNA mutations. Proc Natl Acad Sci U S A, 2005, 102(52): 18769-18770. doi:10.1073/pnas.0509776102. doi: 10.1073/pnas.0509776102. pmid: 16365283
[35]	Van Rie A, Warren R, Richardson M, et al. Classification of drug-resistant tuberculosis in an epidemic area. Lancet, 2000, 356(9223): 22-25. doi:10.1016/S0140-6736(00)02429-6. doi: 10.1016/S0140-6736(00)02429-6. pmid: 10892760
[36]	Field SK. Bedaquiline for the treatment of multidrug-resistant tuberculosis: great promise or disappointment? Ther Adv Chronic Dis, 2015, 6(4):170-184. doi:10.1177/2040622315582325. doi: 10.1177/2040622315582325 pmid: 26137207
[37]	Petrella S, Cambau E, Chauffour A, et al. Genetic basis for natural and acquired resistance to the diarylquinoline R207910 in mycobacteria. Antimicrob Agents Chemother, 2006, 50(8): 2853-2856. doi:10.1128/AAC.00244-06. doi: 10.1128/AAC.00244-06. pmid: 16870785
[38]	Ismail N, Rivière E, Limberis J, et al. Genetic variants and their association with phenotypic resistance to bedaquiline in Mycobacterium tuberculosis: a systematic review and individual isolate data analysis. Lancet Microbe, 2021, 2(11): e604-e616.doi:10.1016/s2666-5247(21)00175-0. doi: 10.1016/s2666-5247(21)00175-0.
[39]	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.
[40]	Phelan J, Coll F, McNerney R, et al. Mycobacterium tuberculosis whole genome sequencing and protein structure modelling provides insights into anti-tuberculosis drug resistance. BMC Med, 2016, 14: 31. doi:10.1186/s12916-016-0575-9. doi: 10.1186/s12916-016-0575-9 pmid: 27005572
[41]	Li Y, Fu L, Zhang W, et al. The Transcription Factor Rv1453 Regulates the Expression of qor and Confers Resistant to Clofazimine in Mycobacterium tuberculosis. Infect Drug Resist, 2021, 14: 3937-3948. doi:10.2147/IDR.S324043. doi: 10.2147/IDR.S324043. URL
[42]	Ismail NA, Omar SV, Moultrie H, et al. Assessment of epidemiological and genetic characteristics and clinical outcomes of resistance to bedaquiline in patients treated for rifampicin-resistant tuberculosis: a cross-sectional and longitudinal study. Lancet Infect Dis, 2022, 22(4): 496-506. doi:10.1016/S1473-3099(21)00470-9. doi: 10.1016/S1473-3099(21)00470-9. URL
[43]	Milano A, Pasca MR, Provvedi R, et al. Azole resistance in Mycobacterium tuberculosis is mediated by the MmpS5-MmpL 5 efflux system. Tuberculosis (Edinb), 2009, 89(1): 84-90. doi:10.1016/j.tube.2008.08.003. doi: 10.1016/j.tube.2008.08.003. URL
[44]	Wells RM, Jones CM, Xi Z, et al. Discovery of a siderophore export system essential for virulence of Mycobacterium tuberculosis. PLoS Pathog, 2013, 9(1): e1003120. doi:10.1371/journal.ppat.1003120. doi: 10.1371/journal.ppat.1003120.
[45]	Fang Z, Sampson SL, Warren RM, et al. Iron acquisition strategies in mycobacteria. Tuberculosis (Edinb), 2015, 95(2): 123-130. doi:10.1016/j.tube.2015.01.004. doi: 10.1016/j.tube.2015.01.004. URL
[46]	Villellas C, Coeck N, Meehan CJ, et al. Unexpected high prevalence of resistance-associated Rv0678 variants in MDR-TB patients without documented prior use of clofazimine or bedaqui-line. J Antimicrob Chemother, 2017, 72(3): 684-690. doi:10.1093/jac/dkw502. doi: 10.1093/jac/dkw502 pmid: 28031270
[47]	Andries K, Villellas C, Coeck N, et al. Acquired resistance of Mycobacterium tuberculosis to bedaquiline. PLoS One, 2014, 9(7): e102135. doi:10.1371/journal.pone.0102135. doi: 10.1371/journal.pone.0102135.
[48]	Gupta S, Tyagi S, Bishai WR. Verapamil increases the bactericidal activity of bedaquiline against Mycobacterium tuberculosis in a mouse model. Antimicrob Agents Chemother, 2015, 59(1): 673-676. doi:10.1128/AAC.04019-14. doi: 10.1128/AAC.04019-14. URL
[49]	Kadura S, King N, Nakhoul M, et al. Systematic review of mutations associated with resistance to the new and repurposed Mycobacterium tuberculosis drugs bedaquiline, clofazimine, linezolid, delamanid and pretomanid. J Antimicrob Chemother, 2020, 75(8): 2031-2043. doi:10.1093/jac/dkaa136. doi: 10.1093/jac/dkaa136 pmid: 32361756
[50]	D’Ambrosio L, Tadolini M, Dupasquier S, et al. ERS/WHO tuberculosis consilium: reporting of the initial 10 cases. Eur Respir J, 2014, 43(1): 286-289. doi:10.1183/09031936.00125813. doi: 10.1183/09031936.00125813 pmid: 24072213
[51]	Ioerger TR, Feng Y, Chen X, et al. The non-clonality of drug resistance in Beijing-genotype isolates of Mycobacterium tuberculosis from the Western Cape of South Africa. BMC Geno-mics, 2010, 11: 670. doi:10.1186/1471-2164-11-670. doi: 10.1186/1471-2164-11-670.
[52]	Richard M, Gutiérrez AV, Viljoen A, et al. Mutations in the MAB_2299c TetR Regulator Confer Cross-Resistance to Clofazimine and Bedaquiline in Mycobacterium abscessus. Antimicrob Agents Chemother, 2019, 63(1): e01316-18. doi:10.1128/AAC.01316-18. doi: 10.1128/AAC.01316-18.
[53]	Alexander DC, Vasireddy R, Vasireddy S, et al. Emergence of mmpT 5 Variants during Bedaquiline Treatment of Mycobacterium intracellulare Lung Disease. J Clin Microbiol, 2017, 55(2): 574-584. doi:10.1128/JCM.02087-16. doi: 10.1128/JCM.02087-16 pmid: 27927925
[54]	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
[55]	de Steenwinkel JE, de Knegt GJ, ten Kate MT, et al. Time-kill kinetics of anti-tuberculosis drugs, and emergence of resistance, in relation to metabolic activity of Mycobacterium tuberculosis. J Antimicrob Chemother, 2010, 65(12): 2582-2589. doi:10.1093/jac/dkq374. doi: 10.1093/jac/dkq374 pmid: 20947621
[56]	Maartens G, Brill MJE, Pandie M, et al. Pharmacokinetic interaction between bedaquiline and clofazimine in patients with drug-resistant tuberculosis. Int J Tuberc Lung Dis, 2018, 22(1): 26-29. doi:10.5588/ijtld.17.0615. doi: 10.5588/ijtld.17.0615 pmid: 29145924
[57]	Gour A, Dogra A, Sharma S, et al. Effect of Disease State on the Pharmacokinetics of Bedaquiline in Renal-Impaired and Diabetic Rats. ACS Omega, 2021, 6(10): 6934-6941. doi:10.1021/acsomega.0c06165. doi: 10.1021/acsomega.0c06165 pmid: 33748607
[58]	Alghamdi WA, Al-Shaer MH, Kipiani M, et al. Pharmacokinetics of bedaquiline, delamanid and clofazimine in patients with multidrug-resistant tuberculosis. J Antimicrob Chemother, 2021, 76(4): 1019-1024. doi:10.1093/jac/dkaa550. doi: 10.1093/jac/dkaa550 pmid: 33378452
[59]	Haas DW, Abdelwahab MT, van Beek SW, et al. Pharmacogenetics of Between-Individual Variability in Plasma Clearance of Bedaquiline and Clofazimine in South Africa. J Infect Dis, 226(1): 147-156. doi:10.1093/infdis/jiac024. doi: 10.1093/infdis/jiac024. URL
[60]	Rivera B, Castellsagué E, Bah I, et al. Biallelic NTHL1 Mutations in a Woman with Multiple Primary Tumors. N Engl J Med, 2015, 373(20): 1985-1986. doi:10.1056/NEJMc1506878. doi: 10.1056/NEJMc1506878. URL
[61]	de Vos M, Ley SD, Wiggins KB, et al. Bedaquiline Microhete-roresistance after Cessation of Tuberculosis Treatment. N Engl J Med, 2019, 380(22): 2178-2180. doi:10.1056/NEJMc1815121. doi: 10.1056/NEJMc1815121. URL
[62]	Li J, Yang G, Cai Q, et al. Safety, efficacy, and serum concentration monitoring of bedaquiline in Chinese patients with multidrug-resistant tuberculosis. Int J Infect Dis, 2021, 110: 179-186. doi:10.1016/j.ijid.2021.07.038. doi: 10.1016/j.ijid.2021.07.038 pmid: 34293490
[63]	Svensson EM, Karlsson MO. Modelling of mycobacterial load reveals bedaquiline’s exposure-response relationship in patients with drug-resistant TB. J Antimicrob Chemother, 2017, 72(12): 3398-3405. doi:10.1093/jac/dkx317. doi: 10.1093/jac/dkx317 pmid: 28961790
[64]	Nahid P, Dorman SE, Alipanah N, et al. Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis. Clin Infect Dis, 2016, 63(7): e147-e195. doi:10.1093/cid/ciw376. doi: 10.1093/cid/ciw376.

药物	基因	基因功能	最低抑菌浓度值
贝达喹啉	atpE	编码ATP合成酶的跨膜蛋白,贝达喹啉的靶蛋白	4~128MIC
氯法齐明	Rv1979c	编码具有渗透酶活性的氨基酸膜转运蛋白	≤4MIC
氯法齐明	Rv1453	编码转录调控蛋白,与qor基因结合	4MIC
贝达喹啉和氯法齐明	Rv0678	调节MmpS5/MmpL5外排泵的表达	2~8MIC
贝达喹啉和氯法齐明	Rv2535c	不确定	4MIC

药物	基因	突变基因
贝达喹啉	atpE	A63P^[21,27]、A28V^[37]、I66M^[37]、A28P^[37]、G61A^[37]、D28N^[26]、A63V^[26]
氯法齐明	Rv1979c	V351A^[19]、V52G^[24]
氯法齐明	Rv1453	res-sacB-hyg-res基因座缺失^[41]
贝达喹啉与氯法齐明	Rv0678	S53L^[24]、S53P^[24]、V1A^[54]、M1A^[54]、S63R^[32]、S63G^[32]、364 C碱基插入^[19]、193G碱基丢失^[19]、W42R^[47]、nt138-144移码突变^[47]、192-199移码突变^[46]、nt212-216移码突变^[47]、nt272-276移码突变^[46]
贝达喹啉与氯法齐明	Rv2535c	c158t^[19]、S53L^[19]、Arg271C缺失^[33]、Ala14 C碱基插入^[33]、L44P^[33]、Ser66Pro^[51]