CN110448693A - 氟喹诺酮类药物作为多粘菌素类抗生素增敏剂的应用 - Google Patents
氟喹诺酮类药物作为多粘菌素类抗生素增敏剂的应用 Download PDFInfo
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- CN110448693A CN110448693A CN201910692481.XA CN201910692481A CN110448693A CN 110448693 A CN110448693 A CN 110448693A CN 201910692481 A CN201910692481 A CN 201910692481A CN 110448693 A CN110448693 A CN 110448693A
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- polymyxin
- colistin
- fluoroquinolones
- pseudomonas aeruginosa
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- 108010040201 Polymyxins Proteins 0.000 title claims description 13
- 230000003115 biocidal effect Effects 0.000 title description 13
- 229940041153 polymyxins Drugs 0.000 title description 3
- 108010093965 Polymyxin B Proteins 0.000 claims abstract description 41
- 229920000024 polymyxin B Polymers 0.000 claims abstract description 41
- 229960005266 polymyxin b Drugs 0.000 claims abstract description 41
- KNIWPHSUTGNZST-UHFFFAOYSA-N polymyxin E2 Natural products CC(C)CCCCC(=O)NC(CCN)C(=O)NC(C(C)O)C(=O)NC(CCN)C(=O)NC1CCNC(=O)C(C(C)O)NC(=O)C(CCN)NC(=O)C(CCN)NC(=O)C(CC(C)C)NC(=O)C(CC(C)C)NC(=O)C(CCN)NC1=O KNIWPHSUTGNZST-UHFFFAOYSA-N 0.000 claims abstract description 30
- 108010078777 Colistin Proteins 0.000 claims abstract description 27
- 241000589517 Pseudomonas aeruginosa Species 0.000 claims abstract description 27
- 229960003346 colistin Drugs 0.000 claims abstract description 27
- JORAUNFTUVJTNG-BSTBCYLQSA-N n-[(2s)-4-amino-1-[[(2s,3r)-1-[[(2s)-4-amino-1-oxo-1-[[(3s,6s,9s,12s,15r,18s,21s)-6,9,18-tris(2-aminoethyl)-3-[(1r)-1-hydroxyethyl]-12,15-bis(2-methylpropyl)-2,5,8,11,14,17,20-heptaoxo-1,4,7,10,13,16,19-heptazacyclotricos-21-yl]amino]butan-2-yl]amino]-3-h Chemical compound CC(C)CCCCC(=O)N[C@@H](CCN)C(=O)N[C@H]([C@@H](C)O)CN[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CCN)NC1=O.CCC(C)CCCCC(=O)N[C@@H](CCN)C(=O)N[C@H]([C@@H](C)O)CN[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CCN)NC1=O JORAUNFTUVJTNG-BSTBCYLQSA-N 0.000 claims abstract description 27
- XDJYMJULXQKGMM-UHFFFAOYSA-N polymyxin E1 Natural products CCC(C)CCCCC(=O)NC(CCN)C(=O)NC(C(C)O)C(=O)NC(CCN)C(=O)NC1CCNC(=O)C(C(C)O)NC(=O)C(CCN)NC(=O)C(CCN)NC(=O)C(CC(C)C)NC(=O)C(CC(C)C)NC(=O)C(CCN)NC1=O XDJYMJULXQKGMM-UHFFFAOYSA-N 0.000 claims abstract description 27
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- 101150026476 PAO1 gene Proteins 0.000 claims abstract description 14
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A61K38/00—Medicinal preparations containing peptides
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
本发明揭示了氟喹诺酮类药物的新用途。即氟喹诺酮类药物在制备铜绿假单胞菌(P.aeruginosa)抑制剂的增敏剂中的应用。其中，所述的氟喹诺酮类药物是吉米沙星，司帕沙星，恩诺沙星，环丙沙星，沙氟沙星，莫西沙星，培氟沙星，妥舒沙星，奥比沙星，普卢利沙星，马波沙星，左氧氟沙星，氟甲喹或/和帕珠沙星；所述铜绿假单胞菌是铜绿假单胞菌DK2或PAO1；所述铜绿假单胞菌抑制剂是多粘菌素B或粘菌素。
Description
技术领域
本发明涉及氟喹诺酮类药物的新用途；具体地说，涉及氟喹诺酮类药物在制备铜绿假单胞菌(P.aeruginosa)抑制剂的增敏剂中的应用。
背景技术
铜绿假单胞菌(P.aeruginosa)是一种严重的可引起危及生命感染的人类病原体。由于过度的内在和获得性抗性机制，多重耐药(MDR)P.aeruginosa对公共健康构成严重威胁。在发达国家，P.aeruginosa负责社区和医院获得性感染，包括医院获得性肺炎(HAP)，呼吸机相关性肺炎(VAP)和血流感染(BSI)(Imperi,Antimicrob.Agents.Chemother.2013,57,996-1005.Puzniak,Antimicrob Agents Chemother.2019,63,e02564.Nagarajan,Chin.Chem.Lett,2014,25,419-422)。此外，P.aeruginosa是囊性纤维化(CysticFibrosis,CF)患者中的常见病原体，易于在该类患者体内建立慢性感染且伴随患者直至生命结束，感染在CF患者中引起极大比例的发病率和死亡率(Anders,Nat.Rev.Microbiol.2012,10,841-851)。P.aeruginosa DK2是自1973年以来从丹麦CF患者体内采集的一种铜绿菌株分离物，其谱系在肺环境中持续存在数十年，在感染患者的同时已发展成独立的亚系统(Marvig,Antimicrob Agents Chemother,2012,56,4519-4521.Yang,Proc Natl Acad Sci U S A,2011,108,7481-7486)。由于极少的抗生素批准和缺乏具有新型作用模式的新抗生素，这类病原体的治疗选择很少。因此，研制能够治疗和/或预防铜绿假单胞菌引起的感染的药物具有临床价值和意义。
多粘菌素(Polymyxin)是一类古老的多肽类抗生素，例如：多粘菌素B(PolymyxinB)和粘菌素(Colistin))，其通过与脂多糖(LPS)核心的脂肪酸和磷酸盐以及革兰氏阴性细菌的脂质A相互作用而引起细胞裂解和死亡(Zhu,Chin.Chem.Lett.2017，28，703-708)。在20世纪80年代早期，Polymyxin类抗生素由于肾毒性发生率很高在大多数地区被废弃使用，随后在过去的30年间，Polymyxin类抗生素再次被用于治疗感染多药耐药革兰氏阴性菌的CF患者。作为慢性感染的CF患者中少数可用且有效的抗生素之一，Polymyxin类抗生素被认为是对抗由革兰氏阴性细菌引起危及生命感染的最后一道防线。但随着最近临床实践中使用的增加，Polymyxin抗性已经产生并迅速传播(Nagarajan,Chin.Chem.Lett,2014,25,419-422.Zhu,Chin.Chem.Lett.2017,28,703-708)。
应对抗药性的紧急情况有两种应对策略，一种是研究一种新型抗生素，具有针对抗性菌株的新型作用模式，但该策略研发周期长，成本高，无法在短时间内缓解临床的困难局面。另一种策略是寻找Polymyxin的增敏剂以恢复抗性菌株对抗生素的敏感性，这种增敏治疗可以保留最后一类抗生素并减少细菌耐药性的产生。重新定位已批准的药物是发现新增敏剂的良好策略，该策略快速有效且成本效益高。
因此，本领域迫切需要一种用于治疗和/或预防由铜绿假单胞菌(P.aeruginosa)引起的细菌感染疾病的Polymyxin类抗生素的增敏剂。同时这也是本发明需要解决的技术问题。
发明内容
氟喹诺酮类药物是目前临床上常用的抗菌药，具有广泛的抗菌谱，主要用于治疗尿路感染、呼吸道等各种组织感染。
本发明的发明人经筛选发现：氟喹诺酮类药物对Polymyxin类抗生素表现出增敏作用。即与某些氟喹诺酮类药物与某些Polymyxin类抗生素联用，对铜绿假单胞菌某些菌株产生优于单独用药的生长抑制作用。
因此，本发明目的一个目的在于，揭示氟喹诺酮类药物的一种新用途：即氟喹诺酮类药物在制备铜绿假单胞菌(P.aeruginosa)抑制剂的增敏剂中的应用；
其中，所述的氟喹诺酮类药物的名称及结构见表1；所述铜绿假单胞菌(P.aeruginosa)是铜绿假单胞菌(P.aeruginosa)DK2(下文简记为“DK2”)或铜绿假单胞菌(P.aeruginosa)PAO1(下文简记为“PAO1”)；所述铜绿假单胞菌(P.aeruginosa)抑制剂是多粘菌素B(Polymyxin B)或粘菌素(Colistin)。
本发明另一个目的在于，提供一种药物组合物。所述药物组合物包含表1所示氟喹诺酮类药物、多粘菌素B(Polymyxin B)或粘菌素(Colistin)和药学上可接受稀释剂和赋形剂等辅料；
其中，氟喹诺酮类药物与多粘菌素B(Polymyxin B)或粘菌素(Colistin)的质量比(0.001～10):1。
此外，本发明还有一个目的在于，公开上述药物组合物的一种用途。即所述药物组合物在制备铜绿假单胞菌(P.aeruginosa)抑制剂的增敏剂中的应用；或，
所述药物组合物在制备治疗和/或预防由铜绿假单胞菌(P.aeruginosa)引起的细菌感染疾病的药物中的应用；
其中，铜绿假单胞菌(P.aeruginosa)是DK2或PAO1；所述铜绿假单胞菌(P.aeruginosa)抑制剂是多粘菌素B(Polymyxin B)或粘菌素(Colistin)；
所述由铜绿假单胞菌(P.aeruginosa)引起的细菌感染疾病包括：由铜绿假单胞菌(P.aeruginosa)感染引起的囊性纤维化，医院获得性肺炎，呼吸机相关性肺炎和血流感染等。
表1
附图说明
图1.为吉米沙星增敏多粘菌素B对PAO1产生生长抑制作用图；
图2.为吉米沙星增加铜绿假单胞菌(P.aeruginosa)细胞外膜的通透性图；
其中，A—吉米沙星增加DK2细胞外膜的通透性图；B—吉米沙星增加PAO1细胞外膜的通透性图。
具体实施方式
下面通过实施例对本发明作进一步阐述，其目的仅在于更好理解本发明的内容，而非限制本发明的保护范围。下列实施例中，DK2的来源为Rau MH,Environ.Microbiol,2012,14,2200-2211，其余菌株、药物和试剂均为市售品。
实施例1
氟喹诺酮类药物增敏多粘菌素B(Polymyxin B)对DK2产生生长抑制作用的棋盘实验。
(1)实验材料和方法
将DK2培养过夜，用新鲜LB培养基稀释至吸光度(OD600)约为0.01。将100μL细菌悬浮液加到96孔板，再加入相应浓度的氟喹诺酮类药物和多粘菌素B，将板在37℃下孵育18小时。分级抑菌浓度(FIC)通过棋盘确定。每种药物的最低抑菌浓度(Minimum InhibitoryConcentration，简记为“MIC”)是肉眼可见无菌生长时的药物浓度。每种药物的FIC计算为(组合使用时药剂的MIC)/(单独使用时药剂的MIC)。FIC指数(FICI)是氟喹诺酮类药物和多粘菌素B的FIC之和。
(2)实验结果
结果见表2。表1所述的氟喹诺酮类药物均可以增敏多粘菌素B，使多粘菌素B的MIC相比单独使用时显著降低，其中吉米沙星，司帕沙星，恩诺沙星，环丙沙星，沙氟沙星，莫西沙星和帕珠沙星能够将多粘菌素B的MIC降低至敏感点(2μg/mL)以下，使耐药DK2恢复对多粘菌素B的敏感性。
其中，FICI为1表明没有相互作用，FICI小于或等于0.5有增敏作用，FICI大于或等于4有拮抗作用。对于DK2，单独使用多粘菌素B时的MIC是512μg/mL，说明DK2对多粘菌素B已经严重耐药。
表2
续表2
a指对于DK2，单独使用氟喹诺酮类药物的MIC。
b指对于DK2，与1μg/mL的氟喹诺酮类药物联用时多粘菌素B的MIC。
c多粘菌素B对铜绿的MIC敏感点≤2μg/mL，耐药点≥8μg/mL；
环丙沙星对铜绿的MIC敏感点≤1μg/mL，耐药点≥4μg/mL；左氧氟沙星对铜绿的MIC敏感点≤2μg/mL，耐药点≥8μg/mL(Wayne,CLSI 2017Document M100-S27)。
d我们将环丙沙星对铜绿的MIC断点应用于吉米沙星，司帕沙星，恩诺沙星，沙氟沙星，莫西沙星，培氟沙星，妥舒沙星，奥比沙星，普卢利沙星，马波沙星，氟甲喹和帕珠沙星。敏感点≤1μg/mL，耐药点≥4μg/mL。
由表2可知：吉米沙星表现出对多粘菌素B最优的增敏作用，能将多粘菌素B的MIC降低4096倍(512μg/mL至0.125μg/mL)。
实施例2
吉米沙星增敏多粘菌素B抑制DK2生长具有浓度依赖性的实验。
(1)实验材料和方法：同“实施例1”。
(2)实验结果：结果见表3。
表3
a指对于DK2，与相应浓度的吉米沙星联用时多粘菌素B的MIC。
由表3可知，吉米沙星可以浓度依赖性的增敏多粘菌素B对DK2产生生长抑制作用，其中吉米沙星为1μg/mL时增敏作用最好。
实施例3
吉米沙星、恩诺沙星和司帕沙星增敏粘菌素(Colistin)对DK2产生生长抑制作用的实验。
(1)实验材料和方法：同“实施例1”。对于DK2，单独使用粘菌素时的MIC>1024μg/mL(说明DK2对粘菌素也已经严重耐药)。
(2)实验结果：结果如表4所示。
表4
a指对于DK2，单独使用氟喹诺酮类药物的MIC。
b指对于DK2，与1μg/mL的氟喹诺酮药物联用时粘菌素的MIC。
c粘菌素对铜绿的MIC敏感点≤2μg/mL，耐药点≥4μg/mL。
由表4可知，吉米沙星、恩诺沙星和司帕沙星可以增敏粘菌素对DK2产生生长抑制作用。其中吉米沙星和恩诺沙星能将粘菌素的MIC降低至临床使用范围。
实施例4
吉米沙星增敏多粘菌素B(Polymyxin B)对PAO1产生生长抑制作用的时间杀伤动力学实验。
(1)实验材料和方法
将PAO1培养过夜，用新鲜LB培养基稀释至在600nm吸光度(OD600)约为0.01。将3mL细菌悬浮液分配到四个试管中，一个试管中是吉米沙星(0.25×MIC)和多粘菌素B的组合，另外三个试管中是吉米沙星(0.25×MIC)，多粘菌素B和DMSO单独，作为对照。将试管在37℃，250rpm摇床中温育，在0,1,2,4和8小时取出等分试样，在PBS中连续稀释并接种在LB琼脂上。将板孵育24小时并测定CFU/mL。
(2)实验结果：
结果如图1所示。
吉米沙星可以增敏多粘菌素B对PAO1产生生长抑制作用。吉米沙星与多粘菌素B的增敏组合相比单独使用多粘菌素B，细菌数量减少3.7log CFU/mL(>2log CFU/mL)，认为有增敏作用(Ayerbe-Algaba,Front Cell Infect Microbiol,2018,8,e348)。
实施例5
吉米沙星可以增加DK2和PAO1细胞外膜通透性的NPN细胞膜通透性实验。
(1)实验材料和方法
收获中间对数期的每种菌株细胞(OD600～0.5)，洗涤，并重悬于ph 7.2的5mMHEPES缓冲液中。在测量荧光之前，立即将100μL体积的细胞加入100μL含有10μM NPN和1％TritonX-100或10mM EDTA或不同浓度吉米沙星的96孔板的缓冲液中。具有NPN的缀合物未处理的细胞悬浮液充当阴性对照，并且从实验数据中减去光谱读数以解释任何背景荧光。在Tecan Spark 10M读数器上在3分钟内记录该值，激发波长为360nm，发射波长为420nm。每个测定至少进行三次。结果表示为相对荧光单位。
(2)实验结果
结果如图2所示，
由图2可知，吉米沙星具有优于阳性对照EDTA显著增加DK2细胞外膜通透性的能力，具有能够增加PAO1细胞外膜通透性的能力，且这种能力具有浓度依赖性，该结果部分验证了吉米沙星增敏多粘菌素B对DK2和PAO1产生生长抑制作用的机制。
Claims (4)
1.氟喹诺酮类药物在制备铜绿假单胞菌(P.aeruginosa)抑制剂的增敏剂中的应用；
其中，所述的氟喹诺酮类药物是吉米沙星，司帕沙星，恩诺沙星，环丙沙星，沙氟沙星，莫西沙星，培氟沙星，妥舒沙星，奥比沙星，普卢利沙星，马波沙星，左氧氟沙星，氟甲喹或/和帕珠沙星；
所述铜绿假单胞菌(P.aeruginosa)是铜绿假单胞菌(P.aeruginosa)DK2或铜绿假单胞菌(P.aeruginosa)PAO1；
所述铜绿假单胞菌(P.aeruginosa)抑制剂是多粘菌素B(Polymyxin B)或粘菌素(Colistin)。
2.一种药物组合物，其包括：权利要求1所述氟喹诺酮类药物、多粘菌素B(PolymyxinB)或粘菌素(Colistin)和药学上可接受稀释剂和赋形剂；
其中，氟喹诺酮类药物与多粘菌素B(Polymyxin B)或粘菌素(Colistin)的质量比(0.001～10):1。
3.如权利要求2所述的药物组合物在制备铜绿假单胞菌(P.aeruginosa)抑制剂的增敏剂中的应用；或，
所述药物组合物在制备治疗和/或预防由铜绿假单胞菌(P.aeruginosa)引起的细菌感染疾病的药物中的应用；
其中，铜绿假单胞菌(P.aeruginosa)是DK2或PAO1；所述铜绿假单胞菌(P.aeruginosa)抑制剂是多粘菌素B(Polymyxin B)或粘菌素(Colistin)；
所述由铜绿假单胞菌(P.aeruginosa)引起的细菌感染疾病包括：由铜绿假单胞菌(P.aeruginosa)感染引起的囊性纤维化，医院获得性肺炎，呼吸机相关性肺炎和血流感染。
4.如权利要求3所述的用途，其特征在于，其中所用的氟喹诺酮类药物为吉米沙星，司帕沙星，恩诺沙星，环丙沙星，沙氟沙星，莫西沙星或/和帕珠沙星。
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