CN111840509A - Nosiheptide在非结核分枝杆菌感染中的应用 - Google Patents
Nosiheptide在非结核分枝杆菌感染中的应用 Download PDFInfo
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- CN111840509A CN111840509A CN202010737878.9A CN202010737878A CN111840509A CN 111840509 A CN111840509 A CN 111840509A CN 202010737878 A CN202010737878 A CN 202010737878A CN 111840509 A CN111840509 A CN 111840509A
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- mycobacterium
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Abstract
本发明公开Nosiheptide在非结核分枝杆菌感染中的应用。本发明进一步公开了一种用于抑制非结核分枝杆菌的抑菌剂,所述抑菌剂的活性成分为Nosiheptide。本发明公开了Nosiheptide单独作用于非结核分枝杆菌具有很好的杀菌活性,可用于非结核分枝杆菌感染疾病的治疗,对发掘Nosiheptide在防治非结核分枝杆菌感染疾病的新用途具有重要意义。
Description
技术领域
本发明涉及生物技术领域,具体涉及一种Nosiheptide在非结核分枝杆菌感染中的应用。
背景技术
非结核分枝杆菌(non-tuberculous Mycobacteria,NTM),是指除结核分枝杆菌复合群和麻风分枝杆菌以外的分枝杆菌。目前已知的有200余种,为条件致病菌。近些年来,随着细菌分离技术的不断提高和普及、免疫受损宿主感染菌群的变迁等原因,导致NTM感染和相关疾病的发生呈现上升趋势,有文献报道我国培养阳性标本中NTM分离株占分枝杆菌分离株的比例从1979年的4.3%上升至2010年的22.9%。
NTM对抗结核药物具有极高的耐药性,对异烟肼、对氨基水杨酸钠、乙胺丁醇、利福平、链霉素等常用抗结核药物都存在不同程度的耐药,耐药率高达97.46%,且大多菌株同时对多种抗结核药物耐药。所以在按照结核病规范疗程治疗后效果欠佳时,医生往往认为是出现了耐多药结核或广泛耐药结核从而可能延误了病情。目前治疗NTM肺病尚无特效药物,且多数NTM对抗结核药物耐药,治疗效果不佳。常规治疗方法以克拉霉素联合阿米卡星方案为主,该方案虽然能延缓病情发展,但是远期疗效欠佳,药物耐药性较高,导致患者预后较差。因此,在NTM发病率逐年攀升以及严峻的耐药形势下,研发治疗NTM的新型抗生素以及发现现有抗生素的抗NTM活性迫在眉睫。
Nosiheptide是属于硫肽类抗生素,具有很强的抗菌活性,可以抑制革兰氏阳性细菌的生长。其作用机制是与核糖体蛋白L11和23S rRNA结合后干扰转录因子与核糖体的结合,从而抑制蛋白质的合成。然而,其在分枝杆菌中的抑菌活性不明确。
发明内容
本发明的目的是,提供一种能够预防或者治疗非结核分枝杆菌感染的药物。
为了解决以上技术问题,本发明提供了A所示的化合物或其药学上可接受的盐或其药学上可接受的酯的用途,所述用途为P1至P4中的任一种;
P1、式A所示的化合物或其药学上可接受的盐或其药学上可接受的酯在制备非结核分枝杆菌抑菌剂中的应用;
P2、式A所示的化合物或其药学上可接受的盐或其药学上可接受的酯在制备抑制非结核分枝杆菌的产品中的应用;
P3、式A所示的化合物或其药学上可接受的盐或其药学上可接受的酯在抑制非结核分枝杆菌中的应用;
P4、式A所示的化合物或其药学上可接受的盐或其药学上可接受的酯在制备预防和/或治疗非结核分枝杆菌所致疾病的产品中的应用。
上文中,式A所示的化合物包括外消旋体、对映异构体、非对映异构体、互变异构体、多晶型物、假多晶型物、无定形形式、水合物或溶剂合物。
其中,所述非结核分枝杆菌为田野分枝杆菌、龟分枝杆菌、胃分枝杆菌、蟾蜍分枝杆菌、加地斯分枝杆菌、隐蔽分枝杆菌、迪氏分枝杆菌、苏加分枝杆菌、副偶然分枝杆菌、脓肿分枝杆菌、灰尘分枝杆菌、堪萨斯分枝杆菌、戈登分枝杆菌、鸟分枝杆菌、瘰疬分枝杆菌、次要分枝杆菌、千田分枝杆菌、副瘰疬分枝杆菌、古德分枝杆菌、浅黄分枝杆菌、微黄分枝杆菌、诡诈分枝杆菌、楚布分枝杆菌、罗德岛分枝杆菌或奥布分枝杆菌。
本发明还提供一种产品,所述产品的主要活性成分为式A所示的化合物或其药学上可接受的盐或其药学上可接受的酯。
所述产品为抑菌剂,所述抑菌剂的用途为抑制非结核分枝杆菌活性。
所述产品为药品,所述药品的用途为预防和/或治疗非结核分枝杆菌感染。
上文中,所述抑菌剂或者所述药品,除含有式A所示的化合物或其药学上可接受的盐或其药学上可接受的酯外,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,如经直肠和阴道;呼吸道给药,如经鼻腔;粘膜给药。上述给药途径优选的是注射给药。
本发明还提供抑制非结核分枝杆菌感染动物的方法,包括给受体动物施用式A所示的化合物或其药学上可接受的盐或是上述产品以抑制非结核分枝杆菌感染动物。
式A所示的化合物或其药学上可接受的盐或其药学上可接受的酯或所述方法或所述产品在抑制非结核分枝杆菌感染动物中的应用应在本发明的保护范围之内。
本发明还提供预防和/或治疗非结核分枝杆菌所致疾病的方法,包括给受体动物施用式A所示的化合物或其药学上可接受的盐或其药学上可接受的酯或所述产品进行预防和/或治疗非结核分枝杆菌所致疾病。
式A所示的化合物或其药学上可接受的盐或其药学上可接受的酯或所述方法或所述产品在预防和/或治疗非结核分枝杆菌所致疾病的应用也应在本发明的保护范围之内。
所述非结核分枝杆菌为田野分枝杆菌、龟分枝杆菌、胃分枝杆菌、蟾蜍分枝杆菌、加地斯分枝杆菌、隐蔽分枝杆菌、迪氏分枝杆菌、苏加分枝杆菌、副偶然分枝杆菌、脓肿分枝杆菌、灰尘分枝杆菌、堪萨斯分枝杆菌、鸟分枝杆菌、戈登分枝杆菌、瘰疬分枝杆菌、次要分枝杆菌、千田分枝杆菌、副瘰疬分枝杆菌、古德分枝杆菌、浅黄分枝杆菌、微黄分枝杆菌、诡诈分枝杆菌、楚布分枝杆菌、罗德岛分枝杆菌或奥布分枝杆菌。
上文中所述动物可为哺乳动物,如人;所述动物还是可以为除哺乳动物,以外的能被非结核分枝杆菌感染的动物。
实验证明,本发明单独使用Nosiheptide有效抑制非结核分枝杆菌标准组和临床株。本发明首次发现Nosiheptide单独作用于非结核分枝杆菌具有很好的杀菌作用,有明显的抗非结核分枝杆菌的作用,提示该化合物可作为候选药物应用于抗非结核分枝杆菌感染药物的开发,对于防治非结核分枝杆菌具有重要的意义。
附图说明
图1为Nosiheptide对26株脓肿分枝杆菌临床分离株的MIC值分布。
图2为Nosiheptide对THP-1细胞毒性的影响。
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。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。
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。
材料说明:
下述实施例中的田野分枝杆菌(Mycobacterium agri)ATCC27406、龟分枝杆菌(Mycobacterium chelonae)ATCC14472、胃分枝杆菌(Mycobacterium gastri)ATCC15754、蟾蜍分枝杆菌(Mycobacterium xenopi)ATCC19250、加地斯分枝杆菌(Mycobacteriumgadium)ATCC27726、隐蔽分枝杆菌(Mycobacteriumcelatum)ATCC51131、迪氏分枝杆菌(Mycobacterium diernhoferi)ATCC19340、苏加分枝杆菌(Mycobacterium szulgai)ATCC35799、副偶然分枝杆菌(Mycobacterium parafortuitum)ATCC19686、脓肿分枝杆菌(Mycobacterium abscessus)ATCC19977、灰尘分枝杆菌(Mycobacterium pulveris)ATCC35154、堪萨斯分枝杆菌(Mycobacterium kansasii)ATCC12478、戈登分枝杆菌(Mycobacterium gordonae)ATCC14470、鸟分枝杆菌(Mycobacterium avium)ATCC25291、瘰疬分枝杆菌(Mycobacterium scrofulaceum)ATCC19981、次要分枝杆菌(Mycobacteriumtriviale)ATCC23292、千田分枝杆菌(Mycobacterium chitae)ATCC19627、副瘰疬分枝杆菌(Mycobacterium parascrofulaceum)ATCCBAA-614、古德分枝杆菌(Mycobacteriumgoodii)ATCC44492、浅黄分枝杆菌(Mycobacterium gilvum)ATCC43909、微黄分枝杆菌(Mycobacterium flavescens)ATCC14474、诡诈分枝杆菌(Mycobacterium fallax)ATCC35219、楚布分枝杆菌(Mycobacteriumchubuense)ATCC27278、罗德岛分枝杆菌(Mycobacterium rhodesiae)ATCC27024、奥布分枝杆菌(Mycobacterium obuense)ATCC27023、偶然分枝杆菌(Mycobacterium fortuitum)ATCC6841、金色分枝杆菌(Mycobacterium aurum)ATCC23366、爱知分枝杆菌(Mycobacterium aichiense)ATCC27280、耻垢分枝杆菌(Mycobacterium smegmatis)ATCC19420、非产色分枝杆菌(Mycobacterium nonchromogenicum)ATCC19530、母牛分枝杆菌(Mycobacterium vaccae)ATCC15483、草分枝杆菌(Mycobacterium phlei)ATCC11758、东海分枝杆菌(Mycobacteriumtokaiense)ATCC27282、猪分枝杆菌(Mycobacterium porcinum)ATCC33776、土地分枝杆菌(Mycobacterium terrae)ATCC15755、外来分枝杆菌(Mycobacterium peregrinum)ATCC14467、美容品分枝杆菌(Mycobacterium cosmeticum)ATCCBAA-878。上述标准株均能通过国内外商业渠道购买获得,可在美国标准生物品保藏中心(American type culturecollection,ATCC)购买。
Nosiheptide是含硫多肽类抗生素Thiopeptide家族中的成员之一,分子式为C51H43N13O12S6,分子量为1222.36,CAS号为56377-79-8,其结构式如下:
实施案例1、Nosiheptide对37株NTM标准菌株体外抑菌活性检测
1.Nosiheptide对田野分枝杆菌体外抑菌活性检测
1.1Nosiheptid溶液的配制:将Nosiheptid(购自TRC,货号N884000)用二甲亚砜(DMSO)(购自索莱宝,货号:D8371)溶解,配制8mg/ml的Nosiheptid母液,过滤除菌,-20℃保存。将Nosiheptid母液用MH培养基(购自BD公司,货号:212322)配置成浓度为16μg/mL的Nosiheptide溶液。在96孔板的第1列加入200μl浓度为16μg/mL的Nosiheptide溶液,吹打混匀后,从第1列孔中吸出100μl至第2列中,依次梯度稀释至第10列后,吸出100μl弃掉;在第11列和12列分别加入100μl和200μl MH培养基,作为对照孔。每个浓度设置2个复孔,进行3次重复实验。
1.2.菌液的配制:将田野分枝杆菌(Mycobacterium agri,ATCC27406)在中性罗氏培养基中进行培养至对数期,刮取对数期的菌株,将菌落置于磨菌瓶中研磨均匀,用MH培养基稀释菌悬液并比浊至1麦氏,再以1:20的比例加入到MH培养基中混匀后得到田野分枝杆菌悬液。
1.3.分别向第1-11列内每孔加入100μl田野分枝杆菌悬液,使每孔中最终容积均为200μl,菌液终浓度4×105CFU/mL,此时第1-10列内各孔内的最终药物浓度依次为8μg/mL、4μg/mL、2μg/mL、1μg/mL、0.5μg/mL、0.25μg/mL、0.125μg/mL、0.0625μg/mL、0.03125μg/mL、0.01563μg/mL,并设立阳性对照孔(第11列,未加药物的含菌培养基)和阴性对照孔(第12列未加菌液和药物的培养基),每个浓度设置2个复孔,进行3次重复实验。
1.4.将所述96孔板放至37℃温箱中培养,慢生长分枝杆菌培养7天,快生长分枝杆菌培养3天。
1.5.向微孔板中加入20μL阿尔玛蓝(购自Biorad,货号:BUF012B)和50μl5%吐温-80(购自Sigma,货号:P4780-500ML)的预混显色液,37℃继续培养24h后观察96孔板颜色变化。
1.6.判定标准:蓝色孔为无菌生长,粉色孔为有菌生长,阻止颜色由蓝色变为粉红色的最低药物浓记为能抑制非结核分枝杆菌田野分枝杆菌(Mycobacterium agri,ATCC27406)生长的最小抑菌浓度(MIC)。
2.Nosiheptide对36株NTM标准菌株体外抑菌活性检测
将步骤1中的田野分枝杆菌(Mycobacterium agri,ATCC27406)分别替换成表1中的其余36株菌株,其他步骤不变,得到Nosiheptid单独作用于NTM标准株的最低抑菌浓度。如表1所示。
通过体外MIC实验分析,Nosiheptid单独作用于NTM标准株的最低抑菌浓度如表1。从表1中可以看出,Nosiheptid作用于表1中的37种分枝杆菌标准菌株时,Nosiheptid对NTM标准株表现出较好的体外抑菌效果,59.5%(22/37)的菌株MIC≤0.5μg/mL;对临床上常见的致病菌,包括脓肿分枝杆菌、鸟分枝杆菌、堪萨斯分枝杆菌、戈登分枝杆菌的MIC均≤0.25μg/mL。另外,Nosiheptid对少部分分枝杆菌的体外抑菌活性较差,32.4%(12/37)的菌株MIC≥8μg/mL;上述结果提示Nosiheptid对NTM的抑菌活性存在种属差异。
表1
实施例2:Nosiheptide对脓肿分枝杆菌临床分离株抑菌活性检测
1.Nosiheptid溶液的配制:将Nosiheptid(购自TRC,货号N884000)用二甲亚砜(DMSO)(购自索莱宝,货号:D8371)溶解,配制8mg/ml的Nosiheptid母液,过滤除菌,-20℃保存。将Nosiheptid母液用MH培养基(购自BD公司,货号:212322)配置成浓度为8μg/mL的Nosiheptide溶液。在96孔板的第1列加入200μl浓度为8μg/mL的Nosiheptide溶液,吹打混匀后,从第1列孔中吸出100μl至第2列中,依次梯度稀释至第10列后,吸出100μl弃掉;在第11列和12列分别加入100μl和200μl MH培养基,作为对照孔。每个浓度设置2个复孔。
2.菌液的配制:分别将收集的26株脓肿分枝杆菌临床分离株(从临床标本中分离所得菌株,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),在中性罗氏培养基中进行培养至对数期,刮取对数期的菌株,将菌落置于磨菌瓶中研磨均匀,用MH培养基稀释菌悬液并比浊至1麦氏,再以1:20的比例加入到MH培养基中混匀后得到菌悬液。
3.分别向第1-11列内每孔加入100μl步骤2中的菌悬液,使每孔中最终容积均为200μl,菌液终浓度4×105CFU/mL,此时第1-10列内各孔内的最终药物浓度依次为4μg/mL、2μg/mL、1μg/mL、0.5μg/mL、0.25μg/mL、0.125μg/mL、0.0625μg/mL、0.03125μg/mL、0.01563μg/mL、0.00781μg/mL,并设立阳性对照孔(第11列,未加药物的含菌培养基)和阴性对照孔(第12列未加菌液和药物的培养基),每次2个复孔,进行3次重复实验。
4.将所述96孔板放至37℃温箱中,培养3天。
5.向微孔板中加入20μL阿尔玛蓝(购自Biorad,货号:BUF012B)和50μl5%吐温-80(购自Sigma,货号:P4780-500ML)的预混显色液,37℃继续培养24h后观察96孔板颜色变化。
6.判定标准:蓝色孔为无菌生长,粉色孔为有菌生长,阻止颜色由蓝色变为粉红色的最低药物浓记为能抑制脓肿分枝杆菌临床分离株生长的最小抑菌浓度(MIC)。结果发现脓肿分枝杆菌临床分离株的MIC值均≤1μg/ml(见图1),MIC50=0.0625μg/ml,MIC90=0.5μg/ml,从图1可以看出Nosiheptide对于脓肿分枝杆菌临床分离株具有较好的体外抑菌作用。
实施例3、CCK-8法检测Nosiheptide对THP-1细胞的细胞毒性
1.细胞的培养
将处于生长对数期的THP-1细胞(购买于中国科学院细胞库)接种于96孔板(10000个/孔),同时加入100ng/L PMA(购自Sigma公司,货号P1585-1MG)孵育24h,诱导分化为巨噬细胞。
2.Nosiheptide对THP-1细胞的细胞毒性的验证
2.1.分别用浓度10μM、5μM、2.5μM、1.25μM、0μM的Nosiheptide溶液作用于THP-1细胞,200μL/孔,分别孵育12h、24h、36h和48h。每种浓度做三个重复。
2.2.吸出培养基(去掉原有药物影响),每孔加入100ul的不完全培养基及10μlCCK-8溶液(购自索莱宝,货号:CA1210),37℃培养箱内孵育2h后,用酶标仪测定在450nm处的吸光度。
3.活力计算:按照下述公式计算在不同Nosiheptide浓度下培养的THP-1细胞的细胞活力。
细胞活力(%)=[A(加药)-A(空白)]/[A(0加药)-A(空白)]×100
式中,A(加药)表示具有细胞、CCK-8溶液和药物溶液的孔的吸光度;A(空白)表示具有培养基和CCK-8溶液而没有细胞的孔的吸光度;A(0加药)表示具有细胞、CCK-8溶液而没有药物溶液的孔的吸光度,结果如图2所示。
从图2可以看出,当Nosiheptide浓度不高于10uM时,与THP-1孵育24h,细胞的存活率为100%,提示其对细胞毒性较低;当Nosiheptide为10uM时,孵育时间为36h,细胞存活率为76.8%;当Nosiheptide为10uM时,孵育时间为48h,细胞存活率为53.1%。
以上对本发明进行了详述。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。按以下附带的权利要求的范围,可以进行一些基本特征的应用。
Claims (10)
2.根据权利要求1所述的应用,其特征在于:所述非结核分枝杆菌为田野分枝杆菌、龟分枝杆菌、胃分枝杆菌、蟾蜍分枝杆菌、加地斯分枝杆菌、隐蔽分枝杆菌、迪氏分枝杆菌、苏加分枝杆菌、副偶然分枝杆菌、脓肿分枝杆菌、灰尘分枝杆菌、堪萨斯分枝杆菌、戈登分枝杆菌、鸟分枝杆菌、瘰疬分枝杆菌、次要分枝杆菌、千田分枝杆菌、副瘰疬分枝杆菌、古德分枝杆菌、浅黄分枝杆菌、微黄分枝杆菌、诡诈分枝杆菌、楚布分枝杆菌、罗德岛分枝杆菌或奥布分枝杆菌。
3.一种产品,所述产品的主要活性成分为权利要求1中式A所示的化合物或其药学上可接受的盐或其药学上可接受的酯。
4.根据权利要求9所述的产品,其特征在于,所述产品的用途为抑制非结核分枝杆菌活性。
5.根据权利要求9所述的产品,其特征在于,所述产品为药品,所述药品的用途为为预防和/或治疗非结核分枝杆菌感染。
6.抑制非结核分枝杆菌感染动物的方法,包括给受体动物施用权利要求1中式A所示的化合物或其药学上可接受的盐或权利要求3-5任一所述产品以抑制非结核分枝杆菌感染动物。
7.权利要求1中式A所示的化合物或其药学上可接受的盐或其药学上可接受的酯或权利要求6所述方法或权利要求3-5任一所述产品在抑制非结核分枝杆菌感染动物中的应用。
8.预防和/或治疗非结核分枝杆菌所致疾病的方法,包括给受体动物施用权利要求1中式A所示的化合物或其药学上可接受的盐或其药学上可接受的酯或权利要求3-5任一所述产品进行预防和/或治疗非结核分枝杆菌所致疾病。
9.权利要求1中式A所示的化合物或其药学上可接受的盐或其药学上可接受的酯或权利要求5所述方法或权利要求3-5任一所述产品在预防和/或治疗非结核分枝杆菌所致疾病的应用。
10.根据权利要求3-5任一所述的产品或权利要求6-9任一所述的方法,其特征在于:所述非结核分枝杆菌为田野分枝杆菌、龟分枝杆菌、胃分枝杆菌、蟾蜍分枝杆菌、加地斯分枝杆菌、隐蔽分枝杆菌、迪氏分枝杆菌、苏加分枝杆菌、副偶然分枝杆菌、脓肿分枝杆菌、灰尘分枝杆菌、堪萨斯分枝杆菌、戈登分枝杆菌、鸟分枝杆菌、瘰疬分枝杆菌、次要分枝杆菌、千田分枝杆菌、副瘰疬分枝杆菌、古德分枝杆菌、浅黄分枝杆菌、微黄分枝杆菌、诡诈分枝杆菌、楚布分枝杆菌、罗德岛分枝杆菌或奥布分枝杆菌。
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