CN114259501A - 杀结核菌素在制备脓肿分枝杆菌和/或结核分枝杆菌的抑菌剂中的应用 - Google Patents
杀结核菌素在制备脓肿分枝杆菌和/或结核分枝杆菌的抑菌剂中的应用 Download PDFInfo
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- tuberculosis
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Abstract
本发明涉及医药领域,具体涉及杀结核菌素在制备脓肿分枝杆菌和/或结核分枝杆菌的抑菌剂中的应用。本发明首先公开了杀结核菌素在制备脓肿分枝杆菌和/或结核分枝杆菌的抑菌剂中的应用,进一步公开了用于抑制脓肿分枝杆菌和/或结核分枝杆菌的抑菌剂,所述抑菌剂的活性成分为杀结核菌素。本发明杀结核菌素单独作用于脓肿分枝杆菌和/或单独作用于结核分枝杆菌都具有很好的杀菌活性,可用于结核病的治疗,对脓肿分枝杆菌和/或结核分枝杆菌具有显著的抑制作用,对于防治结核病具有重要的意义。
Description
技术领域
本发明涉及医药领域,具体涉及杀结核菌素在制备脓肿分枝杆菌和/或结核分枝杆菌的抑菌剂中的应用。
背景技术
杀结核菌素(1,Tubercidin,7-deazaadenosine,TUB),分子式为C11H14N4O4,分子量为266.25,其结构式如下:
杀结核菌素是从杀结核链霉菌(Streptomyces tubericidus)发酵液中分离得到的核苷抗生素,是一个吡咯嘧啶核苷天然产物,为最早发现的7-去氮嘌呤核苷天然产物之一,其结构与腺苷的差别仅为N-7改变为C-7。杀结核菌素是通过核苷转运机制,在细胞内代谢为5’-杀结核菌素三磷酸酯,在细胞内DNA和RNA的合成时作为腺苷三磷酸(ATP)的类似物,抑制DNA和RNA的合成,从而阻止蛋白质的表达,具有显著的抗血吸虫、抗菌和抗肿瘤活性。
脓肿分枝杆菌(Mycobacterium.abscessus)属于非结核分枝杆菌,是目前常见致病性非结核分枝杆菌,是仅次于鸟-胞内复合群导致非结核分枝杆菌肺病的主要致病菌。脓肿分枝杆菌对常见的抗结核药物,如对利福平、异烟肼、链霉素、乙胺丁醇等均不同程度耐药。目前,临床推荐的标准治疗方案为克拉霉素/阿奇霉素,联合阿米卡星、亚胺培南或头孢西丁,但临床治疗效果较差,治愈率低,亟待开发有效的药物用于脓肿分枝杆菌病的治疗。
结核病是由结核分枝杆菌(Mycobacterium tuberculosis,MTB)感染,以低热、咳嗽、咳痰、盗汗等为临床表现的感染性疾病,目前全球潜伏感染约20亿,依据2021 年WHO全球结核报告,2020年全球新增结核病约990万例,2020年全球结核病死亡人数约130万例。依据2021年WHO全球结核报告来看MDR 二线药物治疗成功率仅59%,XDR治疗成功率仅52%,我国MDR二线药物治疗成功率仅54%。虽然WHO提出了治疗MDR的三组药物,也有一些新药如Bdq等,但依然存在耐药问题。因此,急需有效的治疗MTB的药物。
发明内容
本发明所要解决的技术问题为如何有效的抑制脓肿分枝杆菌(Mycobacteriumabscessus)和/或结核分枝杆菌(Mycobacterium tuberculosis,MTB)感染。
为解决上述技术问题,本发明提供式Ⅰ所述的化合物或其药学上可接受的盐在制备抑制脓肿分枝杆菌和/或结核分枝杆菌的产品中的应用,
本发明提供式Ⅰ所述的化合物或其药学上可接受的盐在抑制脓肿分枝杆菌和/或结核分枝杆菌中的应用。
本发明提供式Ⅰ所述的化合物或其药学上可接受的盐在制备预防和/或治疗脓肿分枝杆菌和/或结核分枝杆菌所致疾病的产品中的应用。
本发明提供式Ⅰ所述的化合物或其药学上可接受的盐在预防脓肿分枝杆菌和/或结核分枝杆菌中的应用。
本发明提供式Ⅰ所述的化合物或其药学上可接受的盐在制备抑制脓肿分枝杆菌和/或结核分枝杆菌感染动物的产品中的应用。
本发明提供式Ⅰ所述的化合物或其药学上可接受的盐在抑制脓肿分枝杆菌和/或结核分枝杆菌感染动物中的应用。
进一步地,上述的应用中,所述产品可为抑菌剂。
进一步地,上述的应用中,所述抑菌剂的活性成分为式Ⅰ所述的化合物或其药学上可接受的盐。
进一步地,上述的应用中,所述抑菌剂的剂型可为液剂、乳剂、悬浮剂、粉剂、颗粒剂、可湿性粉剂或水分散粒剂。
进一步地,上述的应用中,所述脓肿分枝杆菌为Mycobacterium abscessus,所述结核分枝杆菌为Mycobacterium tuberculosis,MTB。
本发明中,SUS-TB是指敏感结核分枝杆菌。
MDR-TB即耐多药结核分枝杆菌,是指至少同时对异烟肼和利福平耐药。
Pre XDR-TB即早期广泛耐药结核分枝杆菌,是指对任何氟喹诺酮类药物或氨基糖苷类药物耐药的MDR-TB。
XDR-TB,即广泛耐药结核分枝杆菌,是指对任何喹诺酮类药物耐药,以及3种二线注射类药物(卷曲霉素、卡那霉素和阿米卡星)中的至少1种耐药的MDR-TB.。
本发明中,式Ⅰ所述的化合物可为杀结核菌素(1,Tubercidin,7-deazaadenosine,TUB)。
本发明中,所述抑制或预防脓肿分枝杆菌和/或结核分枝杆菌可为非疾病诊断和治疗目的应用。
所述非疾病诊断和治疗目的的应用领域是指疾病病诊断和治疗目的之外的应用领域,例如应用于脓肿分枝杆菌/或结核分枝杆菌的药物筛选。更具体地,例如在筛选对脓肿分枝杆菌/或结核分枝杆菌敏感药物中作为阳性对照使用。
上述抑菌剂中,除含有活性成分外,还可含有适宜的载体或赋形剂。这里的载体材料包括但不限于水溶性载体材料(如聚乙二醇、聚乙烯吡咯烷酮、有机酸等)、难溶性载体材料(如乙基纤维素、胆固醇硬脂酸酯等)、肠溶性载体材料(如醋酸纤维素酞酸酯和羧甲乙纤维素等)。其中优选的是水溶性载体材料。使用这些材料可以制成多种剂型,包括但不限于片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、脂质体、透皮剂、口含片、栓剂、冻干粉针剂等。可以是普通制剂、缓释制剂、控释制剂及各种微粒给药系统。为了将单位给药剂型制成片剂,可以广泛使用本领域公知的各种载体。关于载体的例子是,例如稀释剂与吸收剂,如淀粉、糊精、硫酸钙、乳糖、甘露醇、蔗糖、氯化钠、葡萄糖、尿素、碳酸钙、白陶土、微晶纤维素、硅酸铝等;湿润剂与粘合剂,如水、甘油、聚乙二醇、乙醇、丙醇、淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、紫胶、甲基纤维素、磷酸钾、聚乙烯吡咯烷酮等;崩解剂,例如干燥淀粉、海藻酸盐、琼脂粉、褐藻淀粉、碳酸氢钠与枸橼酸、碳酸钙、聚氧乙烯、山梨糖醇脂肪酸酯、十二烷基磺酸钠、甲基纤维素、乙基纤维素等;崩解抑制剂,例如蔗糖、三硬脂酸甘油酯、可可脂、氢化油等;吸收促进剂,例如季铵盐、十二烷基硫酸钠等;润滑剂,例如滑石粉、二氧化硅、玉米淀粉、硬脂酸盐、硼酸、液体石蜡、聚乙二醇等。还可以将片剂进一步制成包衣片,例如糖包衣片、薄膜包衣片、肠溶包衣片,或双层片和多层片。为了将单位给药剂型制成丸剂,可以广泛使用本领域公知的各种载体。关于载体的例子是,例如稀释剂与吸收剂,如葡萄糖、乳糖、淀粉、可可脂、氢化植物油、聚乙烯吡咯烷酮、Gelucire、高岭土、滑石粉等;粘合剂如阿拉伯胶、黄蓍胶、明胶、乙醇、蜂蜜、液糖、米糊或面糊等;崩解剂,如琼脂粉、干燥淀粉、海藻酸盐、十二烷基磺酸钠、甲基纤维素、乙基纤维素等。为了将单位给药剂型制成栓剂,可以广泛使用本领域公知的各种载体。关于载体的例子是,例如聚乙二醇、卵磷脂、可可脂、高级醇、高级醇的酯、明胶、半合成甘油酯等。为了将单位给药剂型制成注射用制剂,如溶液剂、乳剂、冻干粉针剂和混悬剂,可以使用本领域常用的所有稀释剂,例如,水、乙醇、聚乙二醇、1,3-丙二醇、乙氧基化的异硬脂醇、多氧化的异硬脂醇、聚氧乙烯山梨醇脂肪酸酯等。另外,为了制备等渗注射液,可以向注射用制剂中添加适量的氯化钠、葡萄糖或甘油,此外,还可以添加常规的助溶剂、缓冲剂、pH调节剂等。此外,如需要,也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂、甜味剂或其它材料。使用上述剂型可以经注射给药,包括皮下注射、静脉注射、肌肉注射和腔内注射等;腔道给药,如经鼻腔;粘膜给药。上述给药途径优选的是注射给药。
根据需要,所述抑菌剂中还可添加表面活性剂(如吐温20、吐温80等)、粘合剂、稳定剂(如抗氧化剂)、pH调节剂等。
上文中,所述动物可为哺乳动物,例如人;所述动物还可以除哺乳动物以外的能被脓肿分枝杆菌和/或结核分枝杆菌感染的动物。
本发明以采用微孔板二倍稀释法进行TUB抗脓肿分枝杆菌和/或结核分枝杆菌活性测定。结果表明,TUB对临床分离的脓肿分枝杆菌和/或结核分枝杆菌有较好的抑菌活性。
附图说明
图1为TUB对于18株M.abscessus临床菌株的MIC检测结果。
图2为TUB对于106株MTB临床菌株的MIC检测结果。
图3为TUB对于23株SUS-TB临床菌株的MIC检测结果。
图4为TUB对于33株MDR-TB临床菌株的MIC检测结果。
图5为TUB对于29株Pre XDR-TB临床菌株的MIC检测结果。
图6为TUB对于21株XDR-TB临床菌株的MIC检测结果。
具体实施方式
下面结合具体实施方式对本发明进行进一步的详细描述,给出的实施例仅为了阐明本发明,而不是为了限制本发明的范围。以下提供的实施例可作为本技术领域普通技术人员进行进一步改进的指南,并不以任何方式构成对本发明的限制。
下述实施例中的实验方法,如无特殊说明,均为常规方法,按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。下述实施例中所用的材料、试剂等,如无特殊说明,均可从商业途径得到。
本发明中,Mycobacteroides.abscessus标准株来源为ATCC 19977。
本发明中,Mycobacterium tuberculosis标准株(MTB标准株H37Rv)来源为ATCC27294。
本发明中,18株M.abscessus临床菌株在文献(Yu X,Gao X,Li C,et al.In VitroActivities of Bedaquiline and Delamanid against Nontuberculous MycobacteriaIsolated in Beijing,China.Antimicrob Agents Chemother.2019;63(8):e00031-19.Published 2019Jul 25.doi:10.1128/AAC.00031-19)中公开。公众可从申请人获得上述生物材料,所得上述生物材料只为重复本发明的实验所用,不可作为其它用途使用。
本发明中,106MTB临床菌株在文献(Wang G,Jiang G,Jing W,et al.Prevalenceand molecular characterizations of seven additional drug resistance amongmultidrug-resistant tuberculosis in China:A subsequent study of a nationalsurvey.J Infect. 2021;82(3):371-377.doi:10.1016/j.jinf.2021.02.004)公开。公众可从申请人获得上述生物材料,所得上述生物材料只为重复本发明的实验所用,不可作为其它用途使用。
本发明中,杀结核菌素(TUB)来源于上海陶素生化科技有限公司,其产品编号为T7004,CAS 69-33-0。
实施例1、TUB作用于M.abscessus标准株和MTB标准株的体外抑菌浓度
1.1、TUB作用于M.abscessus标准株的体外抑菌浓度
待测药液的配制:用DMSO溶解杀结核菌素(1,Tubercidin,7-deazaadenosine,TUB,上海陶素生化科技有限公司,T7004/69-33-0),得到TUB浓度为32μg/mL的溶液,该溶液即为待测药液。
(1)在96孔板的每孔中加入100μl Mueller Hinton(MH)培养基(含5%OADC 增菌液)。
(2)完成步骤(1)后,取所述96孔板,在最后列加入100μl浓度为32μg/mL的待测药物溶液(DMSO配置),混匀后吸出100μl加入第11列,依次梯度稀释至第2列后,抽出100μl弃掉,第1列不含药物,为阳性对照孔。每个浓度设置3个复孔。
(3)完成步骤(2)后,取所述96孔板,每孔加入100μl脓肿分枝杆菌标准菌株菌悬液,使每孔中最终容积均为200μl,脓肿分枝杆菌标准菌株含量为2.5×105cfu/mL;各孔内的最终TUB浓度(μg/mL)具体见表1。
其中,脓肿分枝杆菌标准菌株菌悬液制备方法:将脓肿分枝杆菌标准菌株接种于中性罗氏培养基中,37℃温箱中培养1周后刮取中性罗氏培养基上处于生长对数期菌株,用Mueller Hinton(MH)培养基(含5%OADC)稀释。
表1:TUB作用于M.abscessus标准株的MIC测定实验的TUB浓度分布(μg/ml)
(4)完成步骤(3)后,取所述96孔板,每孔加入20μl Alamar Blue检测试剂和 50μl5%Tween 80溶液,然后继续放至37℃温箱中培养24h。
(5)完成步骤(4)后,取所述96孔板,读取最小抑菌浓度(MIC)并计算抑制率。
最小抑菌浓度(MIC)读取方法:最小抑菌浓度(MIC)即为能够抑制90%菌落生长的药物浓度。
结果显示,TUB对脓肿分枝杆菌标准株的MIC为0.25μg/ml。
1.2、TUB作用于MTB标准株的体外抑菌浓度
(1)在96孔板的每孔中加入100μl Middlebrook 7H9 broth medium(7H9)培养基(含10%OADC)。
(2)完成步骤(1)后,取所述96孔板,在最后列加入100μl浓度为32μg/mL的待测药物溶液(采用DMSO配置),混匀后吸出100μl加入第11列,依次梯度稀释至第2 列后,抽出100μl弃掉,第1列不含药物,为阳性对照孔。每个浓度设置2个复孔。
(3)完成步骤(2)后,每孔加入步骤3中100μl结核分枝杆菌标准菌株菌悬液,使每孔中最终容积均为200μl,菌液终浓度2.5×105CFU/mL;各孔内的最终药物浓度具体见表2。37℃温箱中培养7天。
其中,结核分枝杆菌标准菌株菌悬液制备方法:将结核分枝杆菌标准菌株接种于中性罗氏培养基中,37℃温箱中培养1周后刮取中性罗氏培养基上处于生长对数期菌株,磨菌比浊后用7H9培养基(含10%OADC)稀释。
表2:TUB作用于MTB标准株的MIC测定实验的TUB浓度分布(μg/ml)
(4)完成步骤(3)后,取所述96孔板,每孔加入20μl Alamar blue和50μl 5%Tween80,然后继续放至37℃温箱中培养24h。
(5)完成步骤(4)后,取所述96孔板,读取最小抑菌浓度(MIC)并计算抑制率。
最小抑菌浓度(MIC)读取方法:最小抑菌浓度(MIC)即为能够抑制90%菌落生长的药物浓度。
结果显示,TUB对结核分枝杆菌标准株的MIC为4μg/ml。
实施例2、TUB作用于M.abscessus临床株和MTB临床株的体外抑菌浓度
2.1、TUB作用于M.abscessus临床株的体外抑菌浓度
收集18株M.abscessus临床菌株(临床分离菌株,保存于首都医科大学附属北京胸科医院的北京重大疾病临床数据和样本资源库——结核病库,在文献Yu X,Gao X,Li C,etal.In Vitro Activities of Bedaquiline and Delamanid against NontuberculousMycobacteria Isolated in Beijing,China.Antimicrob Agents Chemother. 2019;63(8):e00031-19.Published 2019Jul 25.doi:10.1128/AAC.00031-19.中公开),每株菌株做2次重复,同时设立阳性对照(未加药组)和阴性对照(未加菌的空白培养基组),体外MIC实验(具体操作方法同实施例1)检测TUB对于临床菌株的抑菌活性,发现大部分临床菌株的MIC值范围在0.0156~4μg/ml(见图1),MIC结果如表3所示。 MIC浓度分布统计结果如表4所示。
表明TUB对于M.abscessus临床菌株具有较好的体外抑菌作用。
表3:TUB作用于M.abscessus临床株的体外抑菌浓度(MIC)
表4:TUB作用于M.abscessus临床株的MIC浓度分布统计结果
2.2、TUB作用于MTB临床株的体外抑菌浓度
收集106株MTB临床菌株(临床分离菌株,保存于首都医科大学附属北京胸科医院的北京重大疾病临床数据和样本资源库——结核病库),每株菌株做2次重复,同时设立阳性对照(未加药组)和阴性对照(未加菌的空白培养基组),体外MIC实验(具体操作方法同实施例1)检测TUB对于临床菌株的抑菌活性,发现大部分临床菌株的MIC值范围在0.5~4μg/ml,MTB临床株对TUB较为敏感(见图2)。106 株临床分例菌株的MIC结果如表5-1所示,MIC浓度分布统计结果如表5-2所示。
表5-1:TUB作用于MTB临床株的体外抑菌浓度(MIC)
表5-2:TUB作用于MTB临床株的MIC浓度分布统计结果
其中23株SUS-TB(敏感结核分枝杆菌)MIC浓度分布统计结果如表6所示, MIC值范围在1~8μg/ml(见图3)。
表6:23株SUS-TB(敏感结核分枝杆菌)MIC浓度分布统计结果
其中33株MDR-TB(耐多药结核分枝杆菌)MIC浓度分布统计结果如表7所示, MIC值范围在1~8μg/ml(见图4)。
表7:33株MDR-TB(耐多药结核分枝杆菌)MIC浓度分布统计结果
其中29株Pre XDR-TB(早期广泛耐药结核分枝杆菌)MIC浓度分布统计结果如表8所示,MIC值范围在1~8μg/ml(见图5)。
表8:29株Pre XDR-TB(早期广泛耐药结核分枝杆菌)MIC浓度分布统计结果
其中21株XDR-TB(广泛耐药结核分枝杆菌)MIC浓度分布统计结果如表9 所示,MIC值范围在1~8μg/ml(见图6)。
表9:21株XDR-TB(广泛耐药结核分枝杆菌)MIC浓度分布统计结果
上述结果表明TUB对于MTB临床菌株具有较好的体外抑菌作用。TUB对于 SUS-TB、MDR-TB和Pre-XDR的MIC值均主要集中于0.5~2μg/ml,说明TUB抗 MDR-TB和Pre-XDR的作用与抗SUS-TB相似,TUB可以有效的抑制敏感结核和耐药结核。在XDR中MIC值均主要集中于0.5~2μg/ml,但是有部分XDR的 MIC>8μg/ml,说明TUB可以部分有效的抑制XDR。
以上对本发明进行了详述阐述。对于本领域技术人员来说,在不脱离本发明的宗旨和范围,以及无需进行不必要的实验情况下,可在等同参数、浓度和条件下,在较宽范围内实施本发明。虽然本发明给出了特殊的实施例,应该理解为,可以对本发明作进一步的改进。总之,按本发明的原理,本申请欲包括任何变更、用途或对本发明的改进,包括脱离了本申请中已公开范围,而用本领域已知的常规技术进行的改变。
Claims (9)
2.权利要求1所述的化合物或其药学上可接受的盐在抑制脓肿分枝杆菌和/或结核分枝杆菌中的应用。
3.权利要求1所述的化合物或其药学上可接受的盐在制备预防和/或治疗脓肿分枝杆菌和/或结核分枝杆菌所致疾病的产品中的应用。
4.权利要求1所述的化合物或其药学上可接受的盐在预防脓肿分枝杆菌和/或结核分枝杆菌所致疾病中的应用。
5.权利要求1所述的化合物或其药学上可接受的盐在制备抑制脓肿分枝杆菌和/或结核分枝杆菌感染动物的产品中的应用。
6.权利要求1所述的化合物或其药学上可接受的盐在抑制脓肿分枝杆菌和/或结核分枝杆菌感染动物中的应用。
7.根据权利要求1或权利要求3或权利要求5中任一项所述的应用,其特征在于:所述产品为抑菌剂。
8.根据权利要求7所述的应用,其特征在于:所述抑菌剂的活性成分为权利要求1所述的化合物或其药学上可接受的盐。
9.根据权利要求7或8所述的应用,其特征在于:所述药品的剂型为液剂、乳剂、悬浮剂、粉剂、颗粒剂、可湿性粉剂或水分散粒剂。
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