CN115006391B - 分枝杆菌四氢叶酸还原酶抑制剂在制备抗致病性分枝杆菌药物增效剂中的应用 - Google Patents
分枝杆菌四氢叶酸还原酶抑制剂在制备抗致病性分枝杆菌药物增效剂中的应用 Download PDFInfo
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Abstract
本发明公开了一种抑制分枝杆菌四氢叶酸还原酶的化合物AB‑131作为抗分枝杆菌药物的增效剂的新用途，本发明通过大量实验筛选出化合物AB‑131能够通过与分枝杆菌四氢叶酸还原酶结合并降低四氢叶酸还原酶的酶活性，显著提高抗分枝杆菌药物（叶酸合成拮抗剂）对氨基水杨酸（PAS）和磺胺甲恶唑（SMX）的抗分枝杆菌活性。分枝杆菌四氢叶酸还原酶抑制剂AB‑131有望开发成新的抗致病性分枝杆菌药物的增效剂，具有重要的应用价值。
Description
技术领域
本发明属于生物医药领域，具体地说，本发明涉及化合物AB-131作为分枝杆菌四氢叶酸还原酶抑制剂在制备抗致病性分枝杆菌药物增效剂中的应用。
背景技术
由结核分枝杆菌(Mycobacterium tuberculosis)和非结核分枝杆菌(Non-tuberculosis mycobacteria)感染引起的肺部感染性疾病对人类的生命健康造成了很大的威胁。目前，对于由这些分枝杆菌引起的肺部感染患者的治疗主要采用以利福平、异烟肼、链霉素、吡嗪酰胺和乙胺丁醇等抗菌药物的长期联合治疗方案。多重耐药患者需要至少18至24个月的治疗，疗程期间需要上千粒的昂贵药片和每日注射，不仅给普通家庭带来了沉重的经济和心理负担，而且长期的抗生素联合治疗极易造成致病分枝杆菌耐药性的产生，发现全新的抗耐药菌药物靶标迫在眉睫。
叶酸合成是细菌生长发育过程中重要的生理途径。现有很多抗感染药物都是靶向于细菌叶酸合成过程的关键酶。目前，已经有磺胺类药物通过与对氨基苯甲酸(PABA)竞争二氢蝶酸合成酶(DHPS)，影响二氢叶酸的合成，进而抑制细菌生长和繁殖。抗菌增效剂甲氧苄啶(TMP)选择性抑制细菌的二氢叶酸还原酶(DHFR)活性，使二氢叶酸不能还原为四氢叶酸，进而抑制细菌的生长繁殖；甲氧苄啶与磺胺类药物合用时，可以使细菌叶酸合成受到双重阻断作用，不仅能够增强抗菌力，同时也能减少耐药性的产生；近年来，另一类靶向胸苷酸合成酶(TS)的抗菌增效剂5-氟尿嘧啶(5-FU)和培美曲塞(Pemetrexed)也被成功开发，它们通过阻断由胸苷酸合成酶(TS)催化的脱氧尿苷酸向脱氧胸腺苷酸转化反应阻止细菌正常合成胸腺嘧啶和二氢叶酸再循环起到杀菌增效作用。细菌要正常合成叶酸进而合成相应的必需氨基酸和核苷酸，除了需要二氢蝶酸合成酶(DHPS)、二氢叶酸还原酶(DHFR)和胸苷酸合成酶(TS)等关键催化酶参与外，还需要一类重要的还原酶——四氢叶酸还原酶(MTHFR)。
本发明通过大量实验筛选开发出化合物AB-131，其能够靶向分枝杆菌四氢叶酸还原酶，并降低分枝杆菌四氢叶酸还原酶的酶活性，化合物AB-131与(叶酸合成拮抗剂)对氨基水杨酸、磺胺甲恶唑联用后能显著提高对氨基水杨酸或者磺胺甲恶唑的抗分枝杆菌活性。
发明内容
本发明的目的是在对氨基水杨酸、磺胺甲恶唑等现有抗分枝杆菌药物基础上，通过大量实验筛选出靶向分枝杆菌四氢叶酸还原酶的化合物AB-131，其可以作为对氨基水杨酸、磺胺甲恶唑等现有抗分枝杆菌临床药物的增效剂。
化合物AB-131结构式为：
本申请发现，化合物AB-131能与分枝杆菌四氢叶酸还原酶结合并有效抑制其活性，分枝杆菌四氢叶酸还原酶对细菌生长发育有重要生物学功能。所以，本申请提供了化合物AB-131，其能与分枝杆菌四氢叶酸还原酶结合，并能有效抑制其活性进而发挥对对氨基水杨酸、磺胺甲恶唑等叶酸拮抗剂抗菌活性的增效作用，因此，本发明筛选出化合物AB-131及其衍生物可用于制备分枝杆菌四氢叶酸还原酶抑制剂，并作为对氨基水杨酸、磺胺甲恶唑等叶酸拮抗剂的增效剂。
作为优选方案，将化合物AB-131及其它们衍生物与药学上可接受的载体制备成片剂、颗粒剂、胶囊剂、丸剂、散剂、口服液、注射剂。
有益效果说明：
本发明研究发现，化合物AB-131可有效抑制耻垢分枝杆菌四氢叶酸还原酶的活力(IC50为19.07μM)(如图1)。并且联合化合物AB-131后PAS的MIC值由4μg/ml降低至1μg/ml，联合化合物AB-131后SMX的MIC值由8μg/ml降低至1μg/ml(表1)。这些结果说明，化合物AB-131能与分枝杆菌四氢叶酸还原酶结合并有效抑制其活性进而增强对氨基水杨酸或者磺胺甲恶唑抗分枝杆菌的活性。分枝杆菌是临床上引发细菌感染的重要病原菌，因此，本发明具有重要的临床意义。
附图说明
图1化合物AB-131抑制耻垢分枝杆菌四氢叶酸还原酶的酶活性IC50；
表1对氨基水杨酸或磺胺甲恶唑联用化合物AB-131抗耻垢分枝杆菌的MIC。
具体实施方式
本发明通过大量实验筛选，发现化合物AB-131可以抑制分枝杆菌四氢叶酸还原酶的活性。并且，抗分枝杆菌药物对氨基水杨酸、磺胺甲恶唑联用化合物AB-131后的抗菌效果显著增加。下面结合具体实施对本发明作进一步阐述，但这些实施不应解释为限制本发明。
实施例1化合物AB-131抑制耻垢分枝杆菌四氢叶酸还原酶的酶活性IC50
分析化合物AB-131对四氢叶酸还原酶活性的抑制作用IC50
测试的化合物：化合物AB-131
分枝杆菌四氢叶酸还原酶催化反应原理方程式如下：
NADH能在分枝杆菌四氢叶酸还原酶(MTHFR)的催化下将5,10亚甲基四氢叶酸(5,10-methylene tetrahydrofolate)还原成5-甲基四氢叶酸(5-methyl tetrahydrofolate),可以通过检测底物NADH的消耗(NADH在340nm有特征吸收)测定分枝杆菌四氢叶酸还原酶的酶活性。
测试方法如下：
在用氮气(N2)气体吹扫的标准50mM磷酸钾缓冲液(pH 7.2)中制备138.8μL反应体系，包含3.61μg(MSMEG_6649)耻垢分枝杆菌四氢叶酸还原酶，5,10-亚甲基四氢叶酸终浓度固定在500μM，NADH终浓度固定在100μM，使化合物AB-131的终浓度从0到100μM梯度变化，在室温25℃下，监测15min内340nm处NADH吸光度的降低。根据NADH吸光度的变化计算IC50，利用GraphPad Prism数据分析，每组实验进行3次平行实验。实验结果如图1所示，化合物AB-131可有效抑制耻垢分枝杆菌四氢叶酸还原酶的活力，IC50为19.07μM。
实施例2抗菌药物对氨基水杨酸、磺胺甲恶唑联用化合物AB-131后抗耻垢分枝杆菌效果增强。
测试的化合物：化合物AB-131。
测定方法：运用高通量的96孔阿尔玛蓝(Alamar blue)法检测对氨基水杨酸(PAS)、磺胺甲恶唑(SMX)单用以及两者联用化合物AB-131后的最低抑菌浓度(MIC)。一系列PAS药物(四倍工作浓度)溶液加入96孔板(每个孔加入50μl)，一系列SMX药物(四倍工作浓度)溶液加入96孔板(每个孔加入50μl)，PAS终浓度0.125到32μg/ml，SMX终浓度0.125到32μg/ml，化合物AB-131终浓度2到128μg/ml，每个孔加入100ml菌液，菌液孔、只有培养基孔作为对照。菌液完全清透(代表菌体完全不生长)作为MIC判读标准。实验独立重复三次。实验结果如表1所示，联合化合物AB-131后PAS的MIC值由4μg/ml降低至1μg/ml，联合化合物AB-131后SMX的MIC值由8μg/ml降低至1μg/ml。这些结果说明，化合物AB-131可增加对氨基水杨酸(PAS)和磺胺甲恶唑(SMX)的抗菌活性，起到了一定的协同抗菌的功效。
表1对氨基水杨酸或磺胺甲恶唑联用化合物AB-131抗耻垢分枝杆菌的MIC
以上所述仅是本发明的优选实施方式，不应被视为是对本发明范围的限制。对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，可根据本发明的技术方案及其较佳实施例的描述，做出各种可能的等同改变或润饰，这些改变和润饰也应视为本发明的保护范围。
Claims (2)
1.化合物AB-131在制备提高对氨基水杨酸或者磺胺甲恶唑抗分枝杆菌的药物制剂中的应用；化合物AB-131的结构式为：
。
2.根据权利要求1所述的应用，其特征在于，将化合物AB-131与药学上可接受的载体制备成片剂、颗粒剂、胶囊剂、丸剂、散剂、口服液或注射剂。
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