CN118416042A - Lefamulin在鸟分枝杆菌复合群感染中的应用 - Google Patents
Lefamulin在鸟分枝杆菌复合群感染中的应用 Download PDFInfo
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Abstract
本发明涉及生物医药技术领域，具体公开了Lefamulin在抗鸟分枝杆菌感染中的应用。本发明中的Lefamulin对鸟分枝杆菌标准菌株和临床分离株均具有较好的抑菌活性，对鸟分枝杆菌标准菌株MIC可达0.5μg/mL，对鸟分枝杆菌临床分离株MIC最好可达0.03125μg/mL，拓宽了Lefamulin的应用领域，为鸟分枝杆菌感染治疗提供了新方法。
Description
技术领域
本发明涉及生物医药技术领域，具体涉及一种半合成截短侧耳素类药物在抗鸟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(mycobacterium tuberculosis complex，MTC)和麻风分枝杆菌以外的分枝杆菌，是一种革兰阳性、抗酸、需氧杆菌，广泛存在于土壤、水、灰尘等自然环境中，其中大部分为腐物寄生菌，可分为快速生长的脓肿分枝杆菌(Mycobacteria abscessumcomplex,MAB)、龟分枝杆菌、偶然分枝杆菌和耻垢分枝杆菌；缓慢生长的鸟分枝杆菌(Mycobacteria aviumcomplex,MAC)、堪萨斯分枝杆菌、戈登分枝杆菌、海分枝杆菌等(李祥芳,丁寿鹏,高婧华,等.非结核分枝杆菌的致病机制研究进展[J].中国病原生物学杂志,2022,17(03):352-355.)。目前分离到的非结核分枝杆菌已有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％。其中，在NTM感染患者中，鸟分枝杆菌的临床相关性较高，为70～80％。同时，鸟分枝杆菌也是我国分离率较高的非结核分枝杆菌，分离率高达9.5％。鸟分枝杆菌(Mycobacterium avium,M.avium)于1890年首次从一只患有肺空洞疾病的鸡身上分离出来，人类感染M.avium病例直到1930年才被报导。M.avium作为一种慢生长分枝杆菌，能够对抗宿主巨噬细胞的吞噬作用，可感染人体多个器官，导致肺病、淋巴结病、皮肤软组织病、骨病、播散性NTM病等多种疾病(DALEY CL,IACCARINO J M,LANGE C,et al.Treatment of non-tuberculous mycobacterial pulmonary disease:anofficial ATS/ERS/ESCMID/lDSA clinical practice guideline[J].Clin InfectDis,2020,71(4):905-913.)。
同时，鸟分枝杆菌对抗结核药物具有极高的耐药性，对利福平、链霉素、乙胺丁醇、卷曲霉素等常用抗结核药物都存在不同程度的耐药，对乙胺丁醇耐药可达94.3％，对利福平和莫西沙星的耐药率高达50％，且大多菌株同时对多种抗结核药物耐药。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。目前非结核分枝杆菌肺病的治疗的官方指南推荐MAC肺病的标准治疗方案是以大环内酯类药物(克拉霉素或阿奇霉素)为核心，联合利福平(或利福布汀)、乙胺丁醇和阿米卡星，该方案虽然能延缓病情发展，但Meta分析显示其治愈率很低，仅有60％～69％(NASIRI M J,EBRAHIMI G,AREFZADEH S,et al.Antibiotic therapy success rate in pulmonary Mycobacterium aviumcomplex.A systematic review and meta-analysis[J].Expert RevAnti Infect Ther,2020,18(3):263-273.)。且其药物耐药性较高，导致患者预后较差。因此，寻找标准治疗方案之外的高效抗MAC药物迫在眉睫。
Lefamulin是由Nabriva Therapeutics研发并于2019年8月由FDA批准上市，用于治疗成人社区获得性细菌性肺炎(CABP)。在我国，由住友制药(苏州)有限公司上海分公司研发的Lefamulin，也于2023年11月17日获得国家食品药品监督局批准上市用于治疗成人社区获得性细菌性肺炎。Lefamulin的抗菌机制同其他截短侧耳素类衍生物类似，通过与细菌50S核糖体的23S r RNA结构域V中心部分的肽基转移酶中心的A位点和P位点选择性结合，来抑制细菌蛋白质合成。其独特的作用机制导致分子与靶位点紧密结合，阻碍t RNA的正确定位，从而抑制肽键形成及肽链延长。但如果肽链已经延长，lefamulin就会失效(肖茜雯.Lefamulin(Xenleta)[J].中国药物化学杂志,2020,30(7):451-452；Mercuro N j,VeveM P.Clinical utility of lefamulin:lfnot now,when[J].Curr Infect Dis Rep,2020,22(9):135-140)。Lefamulin的抗菌谱涵盖引起CABP最相关的病原体，包括(1)革兰阳性菌：肺炎链球菌(包括引起下呼吸道感染的多重耐药分离株)、金黄色葡萄球菌(对甲氧西林敏感、耐甲氧西林和耐万古霉素的分离株)；(2)革兰阴性菌：流感嗜血菌(包括产β-内酰胺酶的流感嗜血菌)、嗜肺军团菌和卡他莫拉菌；(3)非典型呼吸道病原体：肺炎支原体(包括对大环内酯类药物敏感和耐药的菌株)和肺炎衣原体(Mendes R E,Farrell D v,Flamm RK,et al.in vitro activity of lefamulin tested against Streptococcus pneumoniaewith defined serotypes,including multidrug-resistant isolates causing lowerrespiratory tract infections in the United States[J].Antimicrob AgentsChemother,2016,60(7):4407-4411；Waites K B,Crabb D M,Dufy L B,et al.In vitroactivities of lefamulin and other antimicrobial agents againstmacrolide.susceptible and macrolde-resistant mycoplasma pneumonlae from theunied States,Europe,and china[J].Antimicrob Agenis Chemother,2017,61(2)e02008-16；Sader H S,Paukner S,lvezic-Schoenfeld 2,et al.Antimicrobialactivity of the novel pleuromutilin antibiotic BC-3781against organismsresponsible for communityacquired respiratory tract infections(CARTls)[J].JAntimicrob Chemother,2012,67(5):1170-1175)。目前，尚未有Lefamulin抑制鸟分枝杆菌的相关报道。
发明内容
本发明发现Lefamulin具有抑制鸟分枝杆菌活性的作用，据此完成本发明。
第一方面，本发明提供一种药物组合物，所述药物组合物包含Lefamulin和另一种抗鸟分枝杆菌感染的药物，
所述药物组合物具有以下至少一种功效：
a)抑制鸟分枝杆菌活性；
b)抗鸟分枝杆菌感染；
c)预防和/或治疗鸟分枝杆菌所致疾病。
进一步，所述的鸟分枝杆菌包括鸟分枝杆菌标准菌株、鸟分枝杆菌临床分离株或鸟分枝杆菌感染的患者携带的鸟分枝杆菌。
进一步，所述药物组合物最低使用浓度不低于其所抑制的鸟分枝杆菌的最小抑菌浓度(MIC)。
进一步，所述另一种抗鸟分枝杆菌感染药物包括抗生素和其他能够有利于抑制或杀灭鸟分枝杆菌或提供患者抵抗力的药物中的一种或多种。
更进一步，所述抗生素包括利福平、链霉素、乙胺丁醇、莫西沙星、克拉霉素和/或阿米卡星中的一种或多种；所述其他药物包括维生素、氨基酸、蛋白质和/或矿物质中的一种或多种。
更进一步，所述药物组合物中还可以加入一种或多种药学上可接受的载体。
更进一步，所述药物组合物可以制成注射液、片剂、粉剂、颗粒剂、胶囊、口服液或药用辅料等多种形式；上述各种剂型的药物均可以按照药学领域的常规方法制备。
更进一步，所述药物组合物可通过注射、渗透、吸收、物理或化学介导的方法导入机体如肌肉、皮内、皮下、静脉或粘膜组织；或是被其他物质混合或包裹后导入机体。
第二方面，本发明提供一种Lefamulin在制备抑制鸟分枝杆菌产品中的应用。
进一步，所述的鸟分枝杆菌包括鸟分枝杆菌标准菌株、鸟分枝杆菌临床分离株或鸟分枝杆菌感染的患者携带的鸟分枝杆菌。
进一步，所述抑制鸟分枝杆菌产品包括药物和/或抑菌剂中的一种或多种。
第三方面，本发明提供一种Lefamulin在制备预防和/或治疗鸟分枝杆菌感染导致的疾病的药物中的应用。
其中Lefamulin通过如下方式发挥作用：
1)Lefamulin抑制鸟分枝杆菌活性；
2)Lefamulin杀灭鸟分枝杆菌。
进一步，所述的鸟分枝杆菌包括鸟分枝杆菌标准菌株、鸟分枝杆菌临床分离株或鸟分枝杆菌感染的患者携带的鸟分枝杆菌。
进一步，所述抗生素包括利福平、链霉素、乙胺丁醇、莫西沙星、克拉霉素和/或阿米卡星中的一种或多种；所述其他药物包括维生素、氨基酸、蛋白质或矿物质中的一种或多种。
更进一步，所述药物组合物中还可以加入一种或多种药学上可接受的载体。
更进一步，所述药物组合物可以制成注射液、片剂、粉剂、颗粒剂、胶囊、口服液或药用辅料等多种形式；上述各种剂型的药物均可以按照药学领域的常规方法制备。
更进一步，所述药物组合物可通过注射、渗透、吸收、物理或化学介导的方法导入机体如肌肉、皮内、皮下、静脉或粘膜组织；或是被其他物质混合或包裹后导入机体。
有益效果
本发明中的Lefamulin对鸟分枝杆菌标准菌株和临床分离株均具有较好的抑菌活性，对鸟分枝杆菌标准菌株MIC可达0.5μg/mL，对鸟分枝杆菌临床分离株MIC最好可达0.03125μg/mL；
本发明拓宽了Lefamulin的应用领域，为鸟分枝杆菌感染治疗提供了新方法。
附图说明
图1为Lefamulin对临床分离的鸟分枝杆菌的MIC浓度分布。
具体实施方式
以下的实施例便于更好地理解本发明，但并不限定本发明。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试验材料，如无特殊说明，均为自常规生化试剂商店购买得到的。以下实施例中的定量试验，均设置三次重复实验，结果取平均值。
术语解释
meta分析：是指将针对同一临床问题的多项独立研究所报告的结果进行定量综合的统计学方法，具有提高统计效能和效应值估计精确度的优点，此外还能解释不同研究结果间的异质性，系统综述非常重要的统计分析方法。
社区获得性细菌性肺炎：(Community acquiredbacterial pneumonia,CABP)是指在医院外罹患的感染性肺实质炎症，包括具有明确潜伏期的病原体感染在入院后于潜伏期内发病的肺炎。其最主要的病原菌是肺炎链球菌，此外，还包括流感嗜血杆菌、卡他莫拉菌及金黄色葡萄球菌等。
截短侧耳素：是20世纪50年代发现的一种具有抗菌活性的天然产物，由高等真菌担子菌刚侧耳属Pleurotsmutilus和Pleurots passeckerianus菌种经深层培养产生的一类具有骈三环骨架的二萜化合物。
鸟分枝杆菌标准菌株：ATCC 25291。
Lefamulin：从MedchemExpress购得，货号：HY-16908A，分子式为C28H45NO5S，CAS号为1350636-82-6。结构式如下：
实施例1、Lefamulin对鸟分枝杆菌标准菌株抑菌活性检测
鸟分枝杆菌标准株菌悬液制备方法：取鸟分枝杆菌标准株接种于中性罗氏培养基中，37℃温箱中培养3～4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Mueller Hinton(MH)培养基(含5％OADC)稀释，备用。
1、在96孔板的每孔中加入100μl MuellerHinton(MH)培养基(含5％OADC)；
2、完成步骤1后，取96孔板，在第一列加入100μl浓度为128μg/mL的待测药物溶液(采用DMSO配置)，混匀后吸出100μl加入第二列，依次梯度稀释至第11列后，取100μl弃掉，最后一列不含药物，为阳性对照孔。每个浓度设置3个复孔。
3、完成步骤2后，取96孔板，每孔加入100μl鸟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4×105CFU/mL；各孔内的最终药物浓度具体见表1。
4、完成步骤3后，将96孔板放至37℃温箱中，培养9天。
5、完成步骤4后，取96孔板，每孔加入20μlALamar blue和50μl 5％Tween 80，37℃温箱中培养24h。
6、完成步骤5后，取96孔板，读取最小抑菌浓度(MIC)并计算抑制率。
表1
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。通过荧光检测(Ex/Em,530nm/600nm)抑制>90％还原型Alamar blue生成的最小药物浓度。
抑制率％＝100％-(检测孔荧光值-背景荧光值)/(生长对照孔荧光值-背景荧光值)×100％。
背景荧光值为阴性对照的荧光值，生长对照孔荧光值为阳性对照的荧光值。
阴性对照为未加药物和菌液的培养基，阳性对照为未加药物的含菌培养基。
结果显示，Lefamulin对鸟分枝杆菌标准株的MIC为0.5μg/mL。
实施例2、Lefamulin对临床分离鸟分枝杆菌菌株抑菌活性检测
临床分离菌株：23株从鸟分枝杆菌感染患者痰标本中分离培养出的菌株，经16SrRNA、hsp65、rpoB、16-23S rRNA间区测序鉴定为鸟分枝杆菌。
待测药物：Lefamulin
按照实施例1中的方法，检测待测药物对23株临床分离鸟分枝杆菌菌株的抑菌活性。
MIC结果如表2所示。MIC浓度分布统计结果如表3和图1所示。
表2
表3
结果表明，Lefamulin对鸟分枝杆菌有较好的抑菌活性，其MIC最好可达0.03125μg/mL，有望在临床治疗鸟分枝杆菌感染疾病中得到新的应用。
Claims (9)
1.一种药物组合物，所述药物组合物包含Lefamulin和另一种抗鸟分枝杆菌感染的药物，所述Lefamulin结构式如下：
2.如权利要求1所述的药物组合物，所述的鸟分枝杆菌包括鸟分枝杆菌标准菌株、鸟分枝杆菌临床分离株或鸟分枝杆菌感染的患者携带的鸟分枝杆菌。
3.如权利要求1或2所述的药物组合物，所述另一种抗鸟分枝杆菌感染药物包括抗生素和其他能够有利于抑制或杀灭鸟分枝杆菌或提供患者抵抗力的药物中的一种或多种。
4.如权利要求3所述的药物组合物，所述抗生素包括利福平、链霉素、乙胺丁醇、莫西沙星、克拉霉素和/或阿米卡星中的一种或多种。
5.如权利要求3所述的药物组合物，所述其他药物包括维生素、氨基酸、蛋白质和/或矿物质中的一种或多种。
6.一种Lefamulin在制备抑制鸟分枝杆菌产品中的应用。
7.如权利要求6所述的抑制鸟分枝杆菌产品，所述产品包括药物和/或抑菌剂中的一种或多种。
8.一种Lefamulin在制备预防和/或治疗鸟分枝杆菌感染导致的疾病的药物中的应用，
其中Lefamulin通过如下方式发挥作用：
1)Lefamulin抑制鸟分枝杆菌活性；
2)Lefamulin杀灭鸟分枝杆菌。
9.如权利要求8所述的应用，所述的鸟分枝杆菌包括鸟分枝杆菌标准菌株、鸟分枝杆菌临床分离株或鸟分枝杆菌感染的患者携带的鸟分枝杆菌。
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