CN115531388B - 治疗结核病的药物组合物 - Google Patents
治疗结核病的药物组合物 Download PDFInfo
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Abstract
本发明公开了一种一种治疗结核病的药物组合物,药物组合物包括贝达喹啉100~400mg、氯苯吩嗪50~300mg、吡嗪酰胺500~3000mg、Q203 50~300mg。这种新颖、全口服的药物组合物作用于氧化磷酸化途径,不仅对敏感结核病有效,而且用于耐药结核病治疗,提高耐药结核病的疗效,减少复发。
Description
技术领域
本发明涉及医药领域。具体涉及一种治疗结核病的药物组合物。
背景技术
结核病(tuberculosis,TB)是由结核分枝杆菌引起的一种慢性呼吸道传染病,严重危害人类的健康,无论是结核病还是耐药结核病,首选治疗方式都是化学治疗。WHO推荐的MDR-TB化疗方案分为短程和长程两类,其中短程化疗方案的疗程一般为9~12个月,临床上治疗敏感结核病的短程化疗方案是异烟肼+利福平+吡嗪酰胺+乙胺丁醇组成的四药组合,则需要6个月的治疗时间;而耐药结核病形势依然严峻,耐药结核病的治疗成功率仅有55%。治疗耐药结核病主要采用毒副作用大的二、三线抗结核药物至少4~6个药物,包括至少一个注射剂,而且需要9~24个月的治疗周期。目前对于耐多药结核病(MDR-TB)患者,特别是广泛耐药结核病患者,存在费用高、疗程长、治愈率低、副作用大和依从性差等严重问题。因此,抗结核药物研发迫切需要缩短疗程、抑制耐药的新化疗方案。
呼吸作用是生命体内最基础的能量代谢活动之一,生命体可以通过呼吸作用将能量物质(糖、氨基酸及脂肪酸等)转化为机体可以直接利用的高能分子三磷酸腺苷(adenosine triphosphate,ATP)。此前研究表明,呼吸链组分可以进一步聚合组装形成超级复合物,促进其之间串联反应的发生,在能量代谢效率和多种生理过程的调控方面具有重要意义。研究表明,结核分枝杆菌依赖氧化磷酸化产生能量生存。在氧化磷酸化过程中,电子从NADH通过II型NADH脱氢酶(NDH-2)进入电子传递链,导致甲萘醌的还原(MK/MKH2),甲萘醌也可通过替代的电子供体如琥珀酸脱氢酶(SDH)而还原。电子从甲萘醌转移到细胞色素bc1复合体,细胞色素bc1复合物与细胞色素aa3型末端氧化酶形成超复合物,后者将电子转移到氧上。氧也可以被细胞色素bd型末端氧化酶还原,直接接受来自甲萘醌的电子。在电子沿着呼吸链传输过程中,质子被泵过膜形成质子动力势(proton motive force,PMF),PMF的能量可以被ATP合成酶用于合成ATP1。
近年研究表明,靶向能量代谢系统能够显著地克服现有药物的耐药问题,其作为治疗耐药结核病的新型药物靶向系统,日渐受到瞩目。当前,治疗耐多药结核新药贝达喹啉(Bedaquiline,BDQ)就是作用于呼吸链系统抑制其能量合成,作用于电子呼吸链能量代谢途径的抑制剂还有如氯苯吩嗪、吩噻嗪类、3-Nitropropanoate、Lysocin E、Ro 48-8071、NM-4、DG70、SQ109、Q203、兰索拉唑、Aurachin D、Microcin J25、Nitazoxaide、吡嗪酰胺等。其中,二芳基喹啉类药物贝达喹啉(Bedaquiline,BDQ)、亚胺吩嗪类药物氯苯吩嗪(Clofazimine,CFZ)、咪唑吡啶类药物Q203、吡嗪酰胺(Pyrazinamide,PZA)作用于氧化磷酸化途径的不同位点,影响结核分枝杆菌的能量代谢。BDQ通过结合c亚基抑制ATP合成酶,使ATP合成减少,导致结核分枝杆菌死亡;CFZ靶向II型NADH脱氢酶(NDH-2),电子开始进入呼吸链,CFZ被NDH-2还原后,自发和氧反应产生活性氧(ROS),从而导致分枝杆菌的死亡。Q203通过结合QcrB亚基抑制细胞色素bc1复合物(qcrB),中断呼吸链的电子传递,迫使结核分枝杆菌使用效率较低的末端氧化酶细胞色素bd;PZA进入人体后被吡嗪酰胺酶或烟酰胺酶水解成具有活性的吡嗪酸(pyrozinoic acid,POA),POA在进入人体时携带了质子,破坏了跨膜质子动力势(Proton motive force,PMF),抑制ATP的合成和膜转运;SQ109具有类似于PZA的PMF解偶联剂的作用,使膜内外PMF降低,导致ATP的合成减少。在我国《耐药结核病化学治疗指南(2019年简版)》中推荐的MDR-TB治疗方案为6个月的左氧氟沙星(或莫西沙星)-贝达喹啉(或利奈唑胺)-氯法齐明-环丝氨酸-吡嗪酰胺(或乙胺丁醇,或丙硫异烟胺)和12~14个月的左氧氟沙星(或莫西沙星)-氯法齐明-环丝氨酸-吡嗪酰胺(或乙胺丁醇,或丙硫异烟胺);也有6个月的莫西沙星(或左氧氟沙星)-氯法齐明-环丝氨酸-阿米卡星(或卷曲霉素)-丙硫异烟胺(或乙胺丁醇,或吡嗪酰胺)和12~14个月的莫西沙星(或左氧氟沙星)-氯法齐明-环丝氨酸-丙硫异烟胺(或乙胺丁醇,或吡嗪酰胺)的联合使用;专利CN115177602A提供一种治疗结核病的药物组合物,由吡法齐明(TBI-166)、贝达喹啉(BDQ)、吡嗪酰胺(PZA)组成,用于耐药结核病治疗,提高耐药结核病的疗效,并减少复发的可能。专利CN115177602A提供了大麻二酚单独或与其它药物如异烟肼、利福平、乙胺丁醇、吡嗪酰胺、卡那霉素,丁胺卡那、喹诺酮类、对氨基水杨酸、贝达喹啉等联合使用,可以显著抑制结核分枝杆菌感染引起的结核病症状,并对耐药结核菌引起的结核病具有显著的抑制作用。专利CN110831630A公开了一种组合物,其包括吡嗪酰胺(Pyrazinamide,PZA)、细胞色素bc1和抑制剂Q203,其干扰结核分枝杆菌呼吸链,这种组合在结核病的治疗中是有利的。
当前虽然有干扰结核分枝杆菌呼吸链的抗细菌剂的单独使用或者组合使用,但是通过作用于氧化磷酸化途径不同位点的药物组合发挥协同作用,比较完全的耗竭结核分枝杆菌的ATP水平从而产生不同于现有化疗方案策略的新型短程方案,实现缩短结核病治疗的总体目标这一策略迄今为止基本上尚未进行实践。临床上首先发现与贝达喹啉耐药相关,并且报道最多的是结核分枝杆菌Rv0678基因突变。我们也首次从未暴露过贝达喹啉和氯苯吩嗪的中国耐药结核病患者体内分离到了Rv0678突变株,导致了贝达喹啉和氯苯吩嗪交叉耐药。2019年WHO将贝达喹啉和氯苯吩嗪分别列为治疗耐多药结核病核心药物中的A组和B组药物,因此新的化疗方案是否对Rv0678突变株有活性至关重要。
发明内容
本发明提供一种新颖、全口服由贝达喹啉、氯苯吩嗪、吡嗪酰胺和Q203组成的作用于氧化磷酸化途径的新化疗方案,不仅对敏感结核病有效,而且用于耐药结核病治疗,提高耐药结核病的疗效,减少复发。
第一方面,本发明提供一种治疗结核病的药物组合物,所述组合物包括贝达喹啉100~400mg、氯苯吩嗪50~300mg、吡嗪酰胺500~3000mg、Q203 50~300mg。
进一步的,所述组合物包括贝达喹啉100~350mg、氯苯吩嗪50~250mg、吡嗪酰胺500~2500mg、Q20350~250mg。
进一步的,所述组合物包括贝达喹啉100~300mg、氯苯吩嗪50~200mg、吡嗪酰胺500~2000mg、Q203 50~200mg。
进一步的,所述组合物包括贝达喹啉100~250mg、氯苯吩嗪50~100mg、吡嗪酰胺500~1000mg、Q20350~100mg。
所述药物组合物是通过氧化磷酸化途径来治疗耐药结核病。
进一步的,所述药物组合物的给药方式为全口服。
第二方面,本发明提供一种治疗结核病的药物制剂,所述药物制剂包含可治疗结核病的药物组合物和药学上可接受的辅料。
进一步的,所述治疗结核病的药物组合物包括贝达喹啉100~400mg、氯苯吩嗪50~300mg、吡嗪酰胺500~3000mg、Q203 50~300mg。
进一步的,所述含有治疗结核病的药物组合物的药物制剂包括多种剂型,所述剂型包括片剂、糖衣片剂、薄膜衣、片剂、肠溶衣片剂、胶囊剂、硬胶囊剂、软胶囊剂、口服液、口含剂、颗粒剂、冲剂、丸剂、散剂、膏剂、丹剂、混悬剂、粉剂、溶液剂。
第三方面,本发明提供一种氧化磷酸化途径的药物组合物在制备治疗结核病的药物中的应用,所述药物组合物包括贝达喹啉100~400mg、氯苯吩嗪50~300mg、吡嗪酰胺500~3000mg、Q203 50~300mg。
具体实施方式
MIC(minimum inhibitory concentration):最低抑菌浓度,是测量抗菌药物的抗菌活性的指标,指在体外培养细菌18至24小时后能抑制培养基内病原菌生长的最低药物浓度。在本发明中,采用该方法检测贝达喹啉(BDQ)、氯苯吩嗪(CFZ)、SQ109对H37Rv标准株和Rv0678突变株进行抑菌测试,目的在于检测这几种药物对Rv0678突变株的活性效果。
贝达喹啉(Bedaquiline,BDQ):该药由美国FDA于2012年12月28日批准上市,是自1974年利福平(RFP)之后的第一个具有新型作用机制的抗结核新药,也是全球首个自20世纪70年代以来被FDA认证通过的明确用于MDR-TB治疗的新药;该药作用于三磷酸腺苷(ATP)合成酶的质子泵(ATP合成酶用于结核分枝杆菌的能量合成),阻滞其传递必需的旋转运动,从而抑制ATP合成酶活性。贝达喹啉在机体内对抗结核分枝杆菌的同时对宿主细胞几乎无毒性。
亚胺吩嗪类药物氯苯吩嗪(Clofazimine,CFZ),是抗结核活性较高的吩嗪类化合物。化学名10-(对-氯苯基)-2,10-二氢-3-(对-氯苯氨基)-2-异丙亚氨基吩嗪。中文别名N,5-二(4-氯苯基)-3,5-二氢-3-(异丙亚氨基)吩嗪-2-胺。英文名CLO-FAZIMINE,简写B663,其中有氯法齐明,氨苯吩嗪等。主治麻风病的药物,同时具有高活性的抗结核活性,细胞外膜上的细胞膜氧化还原呼吸链和离子转运体则被认为是作用的主要靶点。细胞内氧化还原循环和膜破坏是氯苯吩嗪介导的抗菌活性的2个主要机制。
咪唑吡啶类药物Q203:Q203是由韩国Qurient公司研发的一种新型咪唑并吡啶氨基类抗结核药物,为类白色粉末;Q203的作用靶点是细胞色素bcl复合物中的细胞色素b亚基。该复合物能够催化从辅酶Q到细胞色素C的电子传递过程,同时将质子由线粒体基质泵至膜间隙,是ATP合成呼吸电子传递链的重要组成部分。Q203能够结合细胞色素b亚基上的辅酶氧化位点Qp,从而抑制结核分枝杆菌ATP的合成。体外实验证实,Q203能够使活跃期结核分枝杆菌中的ATP迅速耗尽,并破坏处于休眠期细菌的ATP稳态,从而发挥抑菌效果。
吡嗪酰胺(Pyrazinamide,PZA):又名异烟酰胺,为烟酰胺骨架结构类似物,该药物于1936年由Dalmer和Walter在化学合成过程中作为一种中间化合物首次被合成(ELSEVIERLTD et al.,2008),1952年Yeager等人首次发现吡嗪酰胺具有抗结核分枝杆菌活性(Yeager R L etal.,1952);是用于治疗结核病不可或缺的一线抗结核药物(Y Zhang etal.,2003),在酸性条件下可杀灭处于半休眠期结核菌和持留菌,而其他抗结核药物无此疗效(彭红侠等,2016)。吡嗪酰胺是短程化疗方案中重要的抗结核药物,能将治疗时间缩短到6个月标准,缩短治疗时间具有独特的作用,以及对异烟肼和利福平产生耐药性的患者在治疗中起关键作用(Mitchison D A,1985;WanliangShi et al.,2011),与异烟肼、乙胺丁醇和利福平联用,常用于治疗药物敏感性结核病和耐药结核病(World HealthOrganization,2019)。
SQ109:是在ethambutol的基础上改造而来,作为乙胺丁醇(EMB)类似物中筛选出的抗结核新药,在体外实验中表现出与INH和RFP具有协同作用,为治疗肺结核的第二代抗生素中的先导化合物,药代动力学试验也表明,SQ109靶向肺部,特异性作用于肺,具有抗肺结核药物的优异性质。
在一种实施方式中,选择贝达喹啉(BDQ)、氯苯吩嗪(CFZ)、SQ109进行MIC实验,由于其他药物需要在酸性条件,不适宜体外测定,因此在一种实施例中仅针对贝达喹啉(BDQ)、氯苯吩嗪(CFZ)、SQ109做MIC分析,所述检测方式和药物的选择并不影响本发明的成果。
实施例1 MABA法进行氧化磷酸化的药物最低抑菌浓度的测定
在96孔黑色酶标仪板第1列微孔中加入198μL的7H9培养基和2μL的药物储备液,第2列至第11列加入100μL的7H9培养基,第12列加入200μL的7H9培养基。以二倍稀释法将第1列微孔中的药物稀释至第10列,最后向第1至第11列各孔中加入100μL稀释好的菌液,此时各微孔菌液终浓度为1×105CFU/mL。培养至第3天时将96孔黑色酶标仪板从培养箱中取出,向各微孔中添加12.5μL的20%Tween-80溶液和20μL的Alamar blue指示剂后将板子再放回培养箱中继续孵育。次日观察颜色变化,用多功能酶标仪分别以530nm和590nm激发波长测定各孔荧光值,记录各孔颜色,蓝色表示菌株无生长,红色表示有菌生长;MIC表示由蓝色变为红色的最低药物浓度。
结果显示Rv0678突变株可以导致菌株对BDQ和CFZ的MIC值升高,对SQ109没有变化(见表1),即实验结果BDQ、CFZ、SQ109对Rv0678突变株都具有活性。
表1各抗菌药物的MIC测定
实施例2氧化磷酸化途径药物组合对H37Rv感染的C3HeB/FeJ小鼠的活性
H37Rv感染的C3HeB/FeJ小鼠可以形成空洞和干酪样病灶,类似人感染结核形成的空洞。用气溶胶雾化感染10周龄的雌性C3HeB/FeJ小鼠,感染对数生长期的结核分枝杆菌标准株H37Rv的剂量1×107CFU/ml。在感染后的当天(W-6)和第6周(D0),从感染小鼠中各取6只处死,以确定感染初始和治疗开始时小鼠肺部结核分枝杆菌的基线数量。在给药2周(W2)、4周(W4)后各取6只小鼠处死,取肺组织匀浆,以评价各方案的体内杀菌活性。
2.1给药方式
小鼠体重计算所需药量。药物剂量分别为:BDQ(25mg/kg),CFZ(12.5mg/kg),SQ109(25mg/kg),Q203(10mg/kg)PZA(150mg/kg),Pa-824(100mg/kg),Mfx(100mg/kg)。BDQ、CFZ、Q203、Pa-824均以单药的形式溶解或悬浮于0.5%羧甲基纤维素钠(CMC)水溶液中;SQ109以单药的形式先溶解于PEG-400溶液中,PEG-400溶液再以10%的浓度溶解于CMC水溶液中;Mfx,PZA直接以单药的形式溶解于无菌水溶液中。小鼠感染后6周开始给药,每周给药5天(周一到周五),所有药物均在给药前混合均匀,本实验采取灌胃给药的方式。
2.2治疗效果评估
在治疗过程中,根据肺脏的CFU活菌计数结果来评估方案的治疗效果。治疗2周和4周后,每组取6只小鼠解剖。肺组织取出后浸泡于3mL的无菌生理盐水中匀浆,匀浆好的组织悬液按照预期估计的肺载菌量选择合适的稀释度倍比稀释,匀浆原液和5个梯度的稀释液均取0.25mL均匀涂布于添加0.4%活性碳的7H10固体培养板上。因为BDQ及CFZ脂溶性较高会产生组织蓄积,为避免药物蓄积对实验结果的影响,需用活性碳消除残留的BDQ及CFZ。置于37℃含5%二氧化碳的恒温培养箱中培养,2~3日待培养板上的匀浆液干燥,再将培养板继续倒置培养至少4周。
2.3化疗方案治疗的结果
治疗2周后,BCZ、BCZQ和BCZS活性相当,比未治疗组降低约3log10CFU,治疗4周后比未治疗组降低约5log10CFU,而一线抗结核化疗方案利福平+异烟肼+吡嗪酰胺(RHZ)仅能降低2.5log10CFU12,这表明了氧化磷酸化方案的强大杀菌活性。其中由于肺组织的活菌数量庞大,此处肺组织的活菌计数采用log10 CFU计数(见表2)。
表2各组H37Rv感染C3HeB/FeJ小鼠的肺CFU计数
实施例3氧化磷酸化方案在Rv0678突变株感染的BALB/c小鼠中的疗效
3.1实施方式
气溶胶感染6周龄的雌性BALB/c小鼠,感染对数生长期的结核分枝杆菌Rv0678突变株的剂量1×107CFU/ml。在感染后的第2天(D-13)和第14天(D0),从感染小鼠中各取5只处死,以确定感染初始和治疗开始时小鼠肺部结核分枝杆菌的基线数量。药物剂量、溶解及给药方式同实施例2,小鼠感染后14天,每周给药5天。在给药4周(W4)、8周(W8)、12周(W12)后各取5只小鼠处死,取肺组织匀浆,稀释后涂布于含0.4%活性碳的7H10固体培养板培养4周,以评价各方案的体内杀菌活性。在治疗4周、12周停药后每组10只继续饲养12周以观察复发情况。
3.2化疗方案复发的评估
在复发过程中,我们根据肺脏的CFU活菌计数结果和耐药菌株基因位点测序来评估方案的复发结果。小鼠治疗4周和12周后继续饲养12周,每组取10只小鼠解剖。肺组织取出后浸泡于3mL的无菌生理盐水中匀浆。取2mL匀浆好的组织悬液稀释10倍,匀浆原液和1个梯度的稀释液均取0.25mL均匀涂布于添加0.4%活性炭的7H10固体培养板上。剩下的1mL匀浆原液和1个梯度的稀释液均取0.25mL均匀涂布于含1μg/mLBDQ的7H10固体培养板上。置于37℃含5%二氧化碳的恒温培养箱中培养至少4周,含BDQ的7H10固体培养板培养至少6周。对于在含1μg/mLBDQ的7H10固体培养板上长出来的耐药菌落,提取DNA后对Rv0678基因及atpE基因进行测序,同时对单克隆菌株进行抗菌药物BDQ及CFZ的MIC测定。
3.3化疗方案治疗的结果
BDQ单药治疗4周后,相比未给药组小鼠肺组织菌载量降低了0.52log10CFU,BDQ单药治疗8周后,相比未给药组小鼠肺组织菌载量降低了0.81log10CFU,可以看出25mg/kg的BDQ对结核分枝杆菌Rv0678突变株的抗结核活性很低,几乎没有作用。针对靶向氧化磷酸化途径药物化疗方案,治疗4周时,BCZ组小鼠肺组织菌载量相比未给药组降低了2.27log10CFU,BCZS组小鼠肺组织菌载量相比未给药组降低了2.53log10CFU,BCZQ组小鼠肺组织菌载量相比未给药组降低了3.45log10CFU,BCQS组小鼠肺组织菌载量降低了1.43log10CFU。采用Mann-whitney检验进行统计学分析,BCZQ组和BCZ组,BCZQ组和BCZS组,BCZQ组和BCSQ组均存在显著差异(P<0.05)。治疗4周时BCZQ化疗方案的抗结核活性最好(见表3)。
治疗8周时,BCZ组小鼠肺组织菌载量相比未给药组降低了5.07log10CFU,BCZS组小鼠肺组织菌载量相比未给药组降低了5.24log10CFU,BCZQ组小鼠肺组织菌载量相比未给药组降低了6.50log10CFU,BCQS组小鼠肺组织菌载量相比未给药组降低了2.52log10CFU。采用Mann-whitney检验进行统计学分析,发现分别治疗8周后,BCZQ组和BCZ组,BCZQ组和BCZS组,BCZQ组和BCSQ组均存在显著差异(P<0.05)。治疗12周时,BCZ组小鼠肺组织菌载量为0.59log10CFU,5只小鼠中有1只肺组织菌培养阴性。BCZS组小鼠肺组织菌载量为0.34log10CFU,5只小鼠中有1只肺组织菌培养阴性。BCZQ组小鼠肺组织菌载量为0.20log10CFU,5只小鼠中有2只肺组织菌培养阴性。BCQS组小鼠肺组织菌载量为1.92log10CFU,5只小鼠肺组织菌培养全部阳性。综上,治疗4周、8周、12周时,BCZQ化疗方案对Rv0678突变株的抗结核疗效最为显著,BCZS化疗方案活性略好于BCZ(见表3)。
表3各时间点Rv0678突变株感染BALB/c小鼠的肺CFU计数
注:a:1/5只小鼠肺载菌量无菌化;b:1/5只小鼠肺载菌量无菌化;c:2/5只小鼠肺载菌量无菌化。
治疗12周评估复发的含活性炭7H10培养板CFU计数结果(见表4),BCZ组小鼠肺组织菌载量为0.81log10CFU,10只小鼠有5只达到肺载菌量无菌化;BCZS组小鼠肺组织菌载量为1.18log10CFU,10只小鼠有4只达到肺载菌量无菌化;BCZQ组小鼠肺组织菌载量为0.24log10CFU,10只小鼠有9只达到肺载菌量无菌化,复发率10%,而一线抗结核药物治疗5个月后小鼠复发仍为23%13。治疗12周评估复发的各化疗方案在高浓度BDQ的培养板上均没有菌落生长。结果表明BCZQ化疗方案对Rv0678突变株的良好活性,此方案能够缩短治疗疗程,减少复发。各靶向氧化磷酸化途径药物的化疗方案体内都能够抑制BDQ的进一步耐药。
表4复发组各时间点肺CFU计数
注:含碳板:0.4%活性碳的7H10固体培养板;含BDQ板:1μg/ml BDQ的7H10培养板。a:5/10只小鼠肺载菌量无菌化;b:4/10只小鼠肺载菌量无菌化;c:9/10只小鼠肺载菌量无菌化。
治疗4周评估复发的含活性碳7H10培养板,四组小鼠肺组织菌载量相差不大。含1μg/ml BDQ的7H10培养板上,挑取单克隆菌株培养后提取DNA进行基因测序,结果显示所有生长菌株Rv0678基因突变位点没有新的改变,atpE基因也没有发生突变(见表5)。
表5治疗4周复发组各菌株测序情况
注:a:挑选5个单克隆;b:挑选4个单克隆;c:挑选4个单克隆;d:挑选6个单克隆。各单克隆菌株MIC值测定相差不大,结果取平均值。WT:wild type野生型。
由此可见,本发明的组合物BDQ+CFZ+SQ109+Q203在耐药结核病的治疗方面具有显著的预料不到的效果。
Claims (5)
1.一种氧化磷酸化途径的药物组合物在制备治疗耐药结核病药物中的应用,所述氧化磷酸化途径的药物组合物由贝达喹啉100~400mg、氯苯吩嗪50~300mg、吡嗪酰胺500~3000mg和Q203 50~300mg组成。
2.如权利要求1所述的氧化磷酸化途径的药物组合物在制备治疗耐药结核病药物中的应用,所述氧化磷酸化途径的药物组合物由贝达喹啉100~350mg、氯苯吩嗪50~250mg、吡嗪酰胺500~2500mg和Q203 50~250mg组成。
3.如权利要求1所述的氧化磷酸化途径的药物组合物在制备治疗耐药结核病药物中的应用,所述氧化磷酸化途径的药物组合物由贝达喹啉100~300mg、氯苯吩嗪50~200mg、吡嗪酰胺500~2000mg和Q203 50~200mg组成。
4.如权利要求1所述的氧化磷酸化途径的药物组合物在制备治疗耐药结核病药物中的应用,所述氧化磷酸化途径的药物组合物由贝达喹啉100~250mg、氯苯吩嗪50~100mg、吡嗪酰胺500~1000mg和Q203 50~100mg组成。
5.如权利要求1所述的氧化磷酸化途径的药物组合物在制备治疗耐药结核病药物中的应用,所述治疗耐药结核病的药物包括片剂、胶囊剂、口服液、颗粒剂、丸剂、散剂、膏剂、丹剂和粉剂。
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