CN109640977B - ***二酚组合物及其用途 - Google Patents
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- CN109640977B CN109640977B CN201780034444.9A CN201780034444A CN109640977B CN 109640977 B CN109640977 B CN 109640977B CN 201780034444 A CN201780034444 A CN 201780034444A CN 109640977 B CN109640977 B CN 109640977B
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Abstract
本发明涉及***二酚及其组合物作为抗多药抗性细菌如铜绿假单胞菌的抗菌剂的用途。
Description
发明领域
本发明涉及抗菌剂领域。具体地,本发明涉及***素组合物作为抗多药抗性细菌的抗菌剂的用途。
背景技术
生物膜是一种结构化的微生物群落,是许多微生物生长的天然存在的一种形式。生物膜形成通常是一个非常快速的过程,其包括几个阶段并涉及通过物理化学相互作用调节载体表面以使细胞起始结合到载体表面,产生用于不可逆地将细胞锚定在载体表面上的结合分子(例如细胞外聚合物、粘附素),以小菌落的形式组织细胞群落,并形成和成熟生物膜结构(Masák等,2014,FEMS Microbiol.Ecol.,89:1-14)。这些步骤意味着细胞生理学的显著变化经常导致细胞表型的变化、新代谢途径的发展和毒力因子的表达。通过细胞之间的信号通路实现在菌落内的细胞之间以统一和协调的方式部署这种变化。在假单胞菌中,特别是常见的革兰氏阴性细菌机会性人类病原体,铜绿假单胞菌,参与免疫抑制患者的医院的和危及生命的感染,这种细胞间通信是通过称为群体感应(QS)的基于化学的通信***实现的。通过协调一连串的毒力因子的及时表达与菌落的生长,从而与生物膜形成过程相协调,QS被证明对于控制最初的宿主防御以及对宿主发动恶毒攻势至关重要(Masák等,2014,同上;Juhas等,2005,环境微生物学,7(4):459-471)。此外,在假单胞菌属物种中,生物膜生长通常会增加它们对各种负面环境影响的抗性,因为它们在生物膜内代谢活性较低,因此对抗微生物剂和环境破坏的接受性较低。此外,生物膜形成阻止抗微生物剂进入的物理屏障。因此,这种增加的抗性使它们能够栖息在广泛的小生境中并在土壤基质、植物组织等中定殖(Masák等,2014,同上;Rybtke等,2015,J.Mol.Biol.427:3628-3645)。
由多药抗性(MDR)细菌的细菌生物膜引起的感染,也称为医院感染,已成为大多数医院和医疗机构的主要关注点,因为与单独的潜在疾病相比,它们导致发病率和死亡率增加,并影响患者住院时间和相关医疗费用。
生物膜已被证明是许多组织相关和植入相关感染的潜在的原因(Rybtke等,2015,同上),例如牙齿和颊部感染,例如龋齿、牙周炎、耳炎等耳鼻喉科感染,特别是慢性中耳炎(COM)和慢性鼻窦炎、呼吸道感染如囊性纤维化(CF)和肺炎,尤其是机械通气患者的肺炎,皮肤感染如慢性伤口感染、肌肉骨骼感染,泌尿***和/或***道感染、胆道感染、天然瓣膜心内膜炎、免疫抑制患者(如癌症患者)的机会性感染(Markou等,2014,细胞与感染微生物学前沿期刊,3(115),1-5)和一系列医疗器械相关感染。由铜绿假单胞菌产生的感染的治疗由于生物体的抗性特征而变得复杂并可能导致治疗失败和/或使患者暴露于抗生素药物治疗方案的不良反应。目前用于预防和治疗这些医院感染的药物是广泛的抗菌疗法,然而,由于细菌对许多抗生素的高度抗性,以及它们通过保护其免受药物和免疫***的作用的生物膜的防护而经常发展成致死性感染。具体而言,急性暴发性感染,如菌血症性肺炎、败血症、烧伤创面感染和脑膜炎与极高的死亡率相关。
此外,细菌生物膜形成在食品和化妆品配方污染(Wong等,2000,食品防护杂志,8,1015-1153)、艺术品降解、水污染(Barbeau等,1996,Appl.Environ.Microbiol.,62(11),3954-3959)和医疗器械污染(File等,1995,16(7),417-418)中是个问题。
已经开发了各种方法来调节/抑制假单胞菌生物膜及其形成,其可以包括或不包括干扰生物膜形成的调节机制。群体感应,由于其参与几种毒力因子的表达和铜绿假单胞菌中的生物膜形成,一直是设计用于治疗铜绿假单胞菌感染的新药的有吸引力的靶标(Juhas等,2005,同上)。一些物质已被提出能够干扰群体感应(QS)的机制,如大黄、栀子和穿心莲的水提取物、顺-2-十二碳烯酸、大蒜、普通水果的其他水提取物、草药和香料,白藜芦醇,红霉素,阿奇霉素,克拉霉素和螺旋霉素(Masák等,2014,同上)。然而,目前开发的群体感应抑制剂都没有普遍利用,并且可能需要采取适当的方法,这取决于形成生物膜的位置(Masák等,2014,同上)。
***二酚(CBD)是一种***素,是***植物的主要成分,尤其是***(Canabissativa)(Asthton,2001,英国精神病学杂志,178,101-106)。CBD已被描述为非精神活性物质,其在治疗诸如癫痫、多发性硬化痉挛、焦虑症、精神***症、恶心、惊厥和炎症等疾病以及抑制癌细胞生长方面具有潜在的医学应用。CBD、前CBD以及合成异常CBD(abn-CBD)已被描述为具有抗多种耐甲氧西林金黄色葡萄球菌(MRSA)菌株的活性(Appendino等,2008,天然产物杂志,71:1427-1430)。
由于革兰氏阴性菌如铜绿假单胞菌引起的感染和污染的严重程度,这些细菌对目前抗生素药物的抗性增加,以及一些患者接受此类感染的高风险,非常希望有新的方法来预防和/或治疗革兰氏阴性菌相关的感染,例如医院感染。
发明概述
本发明涉及意外的发现,即***二酚(CBD)对抗多重耐药细菌革兰氏阴性细菌铜绿假单胞菌有活性,因此,例如通过抑制生物膜形成和毒力因子的产生,可用于预防或降低该细菌毒力的程度。因此,CBD可以提供有效的药剂,用于预防和/或治疗由形成多重耐药细菌的细菌生物膜引起的感染或污染。
本发明的一个方面提供CBD或其组合物,其用作针对铜绿假单胞菌的选择性抗菌剂,特别是作为所述细菌形成生物膜的抑制剂。
本发明的另一方面涉及用于预防和/或治疗由铜绿假单胞菌引起的疾病的CBD或其组合物,特别是在预防和/或治疗选自下组的疾病或病症中:医院获得性感染、呼吸道感染、皮肤和软组织感染、伤口感染、牙齿和颊部感染、耳鼻咽喉科感染、泌尿***和/或***道感染、胃肠道感染、胆道感染、眼部感染、菌血症、败血症、中枢神经***感染和心内膜炎。
本发明的一个方面提供CBD或其组合物在制备用于预防和/或治疗由铜绿假单胞菌引起的疾病的药物制剂中的用途,特别是在预防和/或治疗选自下组的疾病或病症中的用途:医院获得性感染、呼吸道感染、皮肤和软组织感染、伤口感染、牙齿和颊部感染、耳鼻咽喉科感染、泌尿***和/或***道感染、胃肠道感染、胆道感染、眼部感染、菌血症、败血症、中枢神经***感染和心内膜炎。
本发明的另一方面涉及CBD或其组合物作为灭菌剂和/或去污剂的用途,特别是作为医用材料的灭菌剂和/或去污剂,旨在用于医疗,美容或卫生操作的房间或用于人类或兽医用途的制剂。
在一个具体实施方案中,提供了CBD或其组合物用于保护本领域技术的用途。
本发明的另一方面涉及包含CBD的去污组合物,特别是包含浓度为约0.1μg/mL至200mg/mL的CBD,例如约0.1μg/mL至1mg/mL,特别是0.1μg/mL至50μg/mL,更特别是1μg/mL至50μg/mL,以及另外的生理学上可接受的载体、稀释剂或赋形剂。
本发明的另一方面涉及包含CBD的灭菌组合物,特别是包含浓度为约0.1μg/mL至200mg/mL的CBD,例如约0.1μg/mL至1mg/mL,特别是0.1μg/mL至50μg/mL,更特别是1μg/mL至50μg/mL,以及另外的生理学上可接受的载体、稀释剂或赋形剂。
本发明的另一方面涉及包含CBD或本发明的去污组合物的食品、饮料或化妆品制剂。
本发明的另一方面涉及涂有CBD或其组合物的制品,特别是用于医学、美容或卫生实践或与用于人类或兽医用途的制剂接触的制品。
本发明的另一方面,提供了一种用于去污(例如材料表面或溶液)或灭菌的试剂盒,其包含本发明的CBD、其组合物、和任选的使用说明书。
本发明的另一方面涉及医疗材料的灭菌和/或去污方法,用于医疗、美容或卫生实践的房间或旨在用于人类或兽医用途的制剂,包括使所述材料、房间或与CBD或其组合物的制剂,特别是与CBD或其组合物接触的步骤,其浓度为约0.1μg/mL至200mg/mL。
另一方面,提供了一种预防或抑制铜绿假单胞菌毒力或其生物膜形成的方法,所述方法包括使易受铜绿假单胞菌污染的表面或组织与CBD或其组合物,特别是CBD或其组合物接触,浓度为约0.1μg/mL至200mg/mL。
另一方面,提供了一种抑制所述铜绿假单胞菌的毒力和/或该细菌形成生物膜的方法,特别是离体方法,所述方法包括使含有该细菌和/或其生物膜的材料或溶液与CBD或其组合物接触的步骤。
本发明的另一方面涉及预防和/或治疗由铜绿假单胞菌引起的疾病的方法,特别是选自下组的疾病或病症:医院获得性感染、呼吸道感染、皮肤和软组织感染、伤口感染、牙齿和颊部感染、耳鼻咽喉科感染、泌尿***和/或***道感染、胃肠道感染、胆道感染、眼部感染、菌血症、败血症、中枢神经***感染和心内膜炎,所述方法包括将治疗有效量的本发明的CBD或其组合物给予有需要的受试者,特别是当CBD或其组合物的浓度为约0.1μg/mL至200mg/mL,例如约0.1μg/mL至1mg/mL,特别是0.1μg/mL至50μg/mL,更特别是1μg/mL至50μg/mL。
本发明的另一方面涉及一种用于保护艺术作品的方法,例如绘画和古董手稿,包括使所述艺术品与CBD或其组合物接触的步骤。
附图说明
图1显示了与在没有CBD的情况下来自wt或来自wt或来自铜绿假单胞菌ΔlasIΔrhlI突变体的弹性蛋白酶的酶活性相比较,实施例2中所述的在500μg/mlCBD存在下孵育的铜绿假单胞菌PAOW1(PT5)(wt)产生的弹性蛋白酶的相对弹性蛋白酶活性。
图2显示了如实施例3中所述,在存在CBD的情况下与铜绿假单胞菌的群体感应***相关的基因表达的倍数诱导(FI)。
发明详述
术语“医院获得性感染(HAI)”或“医院感染”是指从医疗机构(例如医院、疗养院、康复机构、诊所)的环境或工作人员感染的感染。感染传播的主要途径包括接触传播(例如,在需要直接个人接触的病人护理活动期间,受污染的器械、针头、手套或敷料)、液滴或空气传播、普通载体传播(例如受污染的食物、水、药物、装置和设备)。在某些情况下,微生物来自患者自身的皮肤或肠道微生物群,在手术或其他损害保护性皮肤或肠道屏障的程序后变得有机会,尽管患者可能已经从自己的皮肤或肠道感染了感染,但感染被认为是医院内的,因为它在医疗保健环境中发展。
术语“毒力因子”是由细菌产生的分子,其有助于其致病性,例如粘附素、侵袭素和抗吞噬因子,用于定殖宿主或毒素、溶血素和蛋白酶,其损害宿主。
如本文所用,术语“生物膜”是指结构化的微生物群,其中细胞彼此粘附,并且这些细胞通常粘附于表面。与其他革兰氏阴性细菌一样,铜绿假单胞菌以称为结构化生物膜的聚集体的形式生长,其中细胞用由细胞外聚合物组成的复合基质包被。
术语“群体感应(QS)”是指导致响应细胞群密度波动而调节基因表达的机制。群体感应细菌产生并释放化学信号分子(自诱导物),其作为细胞密度的函数而增加浓度,并且检测自诱导剂的阈值刺激浓度导致基因表达的改变。可以发现多种不同的分子作为信号,包括寡肽N-酰基高丝氨酸内酯(AHL)和在革兰氏阴性细菌中称为自诱导剂-2(AI-2)的一系列自诱导物。群体感应可以发生在单个细菌物种内以及不同物种之间。细菌使用群体感应通信电路来调节多种生理活动,这些活动包括共生、毒力、能力、结合、抗生素产生、运动、孢子形成和生物膜形成。铜绿假单胞菌具有两种已知的基于酰基高丝氨酸内酯(AHL)分子的群体感应***,这是las***和rhl***以及基于喹诺酮的***。las***由转录激活因子LasR和AHL合酶LasI组成,其指导N-3-氧代-十二烷酰基-高丝氨酸内酯(3-氧代-C12-HSL)的合成。rhl***由转录调节因子RhlR和AHL合酶RhlI组成,其指导N-丁酰基-高丝氨酸内酯(C4-HSL)的合成。las***被认为是生物膜成熟和分化的关键因素,rhl***负责生产生物表面活性剂(鼠李糖脂),其是维持假单胞菌生物膜中的开放通道***所必需的。此外,基于喹诺酮的***是基于信号分子2-庚基-3-羟基-4-(1H)-喹诺酮(称为假单胞菌喹诺酮信号)(Juhas等,2005,同上;Masák等,2014,同上)。
术语“群体感应抑制”是指对群体感应过程的抑制或减弱。通过对群体感应机制的作用对细菌毒力的药剂的抑制活性可以通过例如它们对生物膜形成的影响进行间接评估(例如通过测量生物膜质量的读数,例如染色、DNA定量共聚焦激光扫描显微镜来分析生物膜的形态)或更直接地对群体感应信号组件,例如通过量化参与群体感应信号的基因的mRNA水平和毒力因子(例如,AHL(N-酰基高丝氨酸内酯)产生、QS基因活性、毒力因子产生(Las A,LasB和水溶性荧光素(pyoverdin))和生长曲线研究和Bradford测定的测定。
用作群体感应抑制剂的物质的实例包括减少信号分子产生或抑制其受体的药剂。
术语“抗菌化合物”是指抑制微生物生长和发育的物质。
术语“灭菌”是指消除微生物有机体以实现无菌(无菌微生物环境)的过程。
术语“去污”是指清洁物体或物质以除去包含细菌的污染物以防止细菌扩散的过程。
表面材料、房间表面(例如墙壁、地板或房间家具)或样品制备(例如培养基、缓冲溶液、增溶介质、化妆品、药物或食品工业制剂)的术语“污染”,是指通过局部接触、插管或摄取,在这些表面或制剂中存在细菌,其水平被认为对这种材料或样品制剂的使用者有害。
食物或膳食制剂,化妆品制剂或水可被铜绿假单胞菌污染,铜绿假单胞菌可在培育环境(48h)内快速发展并导致例如需氧食物的降解。
如本文所定义的术语“医疗材料”是用于医疗保健的任何材料或设备,例如用于医疗状况材料的辅助诊断、监测或治疗的外科手术或重症监护设备(例如医疗保健用纺织品、医疗场所涂料、管材等......)。它包括导管(如腹膜透析导管和静脉导管)、异物植入物(如假体心脏瓣膜、心脏起搏器、全关节假体、肾透析分流器)、医疗成像机(如超声和核磁共振成像仪、PET和CT扫描仪、X光机)、治疗设备(如输液泵、医用激光、外科手术机)、生命支持设备(如医用呼吸机、麻醉机、心肺机、ECMO和透析机)、医用监护仪(如显示心电图、脑电图和血压)、医学实验室设备(如用于分析血液中的血液、尿液、基因和溶解气体)、诊断设备、治疗设备(如理疗机)、牙科设备(如牙钻)和隐形眼镜。
术语“旨在用于医疗、美容或卫生实践的房间”包括将对受试者或样品或材料制剂进行医学、美容或卫生行为以及需要一定程度的无菌或卫生的任何房间。这些房间包括洁净室(例如药剂、化妆品或食品调理室)、咨询室、产房、急诊室、重症监护病房、产科病房、托儿所、病房、墙四周设置软垫之病室、牙医治疗室和手术室、美容工作室、日光浴沙龙等。
术语“呼吸道感染(或疾病)”通常定义为由细菌,特别是细菌生物膜引起的传染病,其涉及呼吸道并且可以被分类为上呼吸道感染(URI)或下呼吸道道感染(LRI)。可由铜绿假单胞菌引起的呼吸道感染的非限制性实例包括肺炎、伴有微脓肿和组织坏死的双侧肺炎。该术语包括囊性纤维化患者可能发生的所有呼吸道感染,以前使用广谱抗生素治疗的患者,使用(过)通气支持设备的患者(如插管),免疫功能低下的患者,患有慢性肺病、艾滋病或血癌等先前病症的患者(血癌患者接受药物后大多发生呼吸道感染),心脏泵功能失常的患者。
术语“皮肤和软组织感染(或疾病)”通常在此定义为涉及细菌侵入皮肤和下面的软组织的感染或疾病。由铜绿假单胞菌引起的皮肤感染或疾病的实例包括脓皮病、婴儿和儿童脓皮病、坏疽(如四肢、***、面部和咽部上部坏疽),弥漫性皮疹伴有水泡或丘疹和坏疽性肾炎(EG)。该术语包括严重烧伤导致组织坏死的受试者的所有皮肤感染,受伤后、皮肤磨损(如划伤和脱毛)后、与污染水接触后(如蒸汽室、按摩浴缸和游泳池)的受试者,卧床不起的受试者和皮肤感染引起的皮肤炎症(感染性皮炎)。皮肤感染的诱发因素包括外伤、之前患有皮肤病、卫生条件差、宿主免疫力受损(如白细胞减少),以及之前使用广谱抗生素治疗。
术语“伤口感染”和“慢性伤口感染”包括感染如手术伤口感染、脚癣、革兰氏阴性毛囊炎、慢性甲沟炎(绿指甲综合症)、温泉池毛囊炎和坏死性脓疮。
术语“泌尿道和/或***跟踪感染”包括***,例如脓疮和慢性细菌性***炎。这些可能发生在手术后的受试者中,例如,在患有导尿管,或患有***疾病,或任何尿路梗阻或具有泌尿道的解剖学缺陷的受试者和截瘫患者中。
术语“牙齿和颊部感染”包括龋齿和牙周炎。
术语“耳鼻咽喉科感染”包括耳部感染,例如外耳炎,其涉及外耳和耳道,中耳炎,其涉及中耳和中耳炎(耳炎迷路炎)和慢性鼻窦炎。诱发外耳炎发病的因素包括糖尿病和高龄。
术语“眼部感染(或疾病)”包括眼外伤后或眼睛接触污染水或隐形眼镜后的感染。
术语“胃肠道感染”包括胆道感染。
术语“菌血症”是指血流中存在活细菌,并且可能发生在患有中性粒细胞减少症、糖尿病、烧伤、恶性血液病和坏疽性***的受试者中。
术语“败血症”是指感染的并发症,这是一种潜在的严重医学病症,其特征是全身炎症状态(称为全身性炎症反应综合征或SIRS),并且存在已证实的(基于取样或放射学)或可能(考虑患者的临床表现、白细胞计数、CRP、放射学)感染。败血症一词总结了临床表现,其中通常是发热、白细胞增多、意识改变、高动力循环(“暖休克”)和过度代谢状态,主要是观察到微生物侵入正常无菌组织的结果。败血症这一术语对应于来自ACCP/SCCM共识会议委员会的“败血症和器官衰竭的定义和败血症创新疗法使用指南”中定义的败血症定义(Bone等,Chest 1992,101,1644-1655)。
术语“中枢神经***(CNS)感染(或疾病)”包括在涉及进入CNS的手术如腰椎穿刺或脊髓麻醉的头部外伤、手术、步骤后受试者中可能发生的所有CNS感染。中枢神经***感染发展的易诱发因素包括既往感染、既往疾病(如头颈癌)、免疫***受损和高龄。
术语“心内膜炎”或“感染性心内膜炎(IC)”是指心脏内层(心内膜)的炎症,其也可包括心脏瓣膜、室间隔、腱索、壁心内膜或心内装置的表面。
如本文所用的术语“受试者”是指哺乳动物。例如,本发明考虑的哺乳动物包括人、灵长类动物、家养动物如狗、猫、牛、绵羊、猪、马、实验室啮齿动物等。
如本文所用,“治疗(treatment)”和“治疗的(treating)”等通常意指获得所需的药理学和生理学效果。就预防或部分预防细菌感染或其疾病、症状或病症而言,该效果可以是预防性的,和/或就部分或完全治愈细菌感染、由细菌感染引起的疾病、病症、症状或副作用而言,可以是治疗性的。
本发明的治疗或方法的术语“功效”可以基于响应于使用本发明化合物或方法的感染过程、疾病或病症的变化来测定。例如,本发明的治疗或方法的功效可以通过其对感染迹象或症状的影响来测定。当患者经历部分或完全缓解或减少不想要的感染症状时,实现响应。
一方面,本发明的治疗的功效可以通过有效量的CBD对铜绿假单胞菌的毒力的影响来评估,例如对毒力因子的产生,对细菌的生物膜形成和/或群体感应***的影响。根据一个具体方面,本发明的治疗的功效可以通过细菌的群体感应级联的效果(抑制/减少)来测定,而不必杀死它。
如本文所用的术语“有效量”是指在施用所述化合物或制剂的受试者中引起疾病症状的可检测的减少的CBD或其制剂的量。
本发明的化合物
术语“***二酚(CBD)”是指可在***植物中发现的一种***素,具有以下化学结构:
2-[(1R,6R)-6-异丙烯基-3-甲基环己烷-2-烯-1-基]-5-戊基苯-1,3-二醇(2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol),也称为Δ2-***二酚。
它是***植物的主要成分,仅次于THC,其提取物含量高达40%。与THC的对CB1和CB2受体的亲和力非常低相比,它导致该物质不具有精神活性。CBD可以从各种***植物物种中提取,包括***(Cannabis sativa)、籼稻(inda)和蓖麻(ruderalis)。具体地,与天然存在的植物相比,CBD可以从转基因***植物中提取为纯化合物,从而产生更高水平的CBD。
根据一个实施方案,提供了一种天然来源的CBD,其是从***品种中提取的。
根据另一个实施方案,可以通过技术人员已知的标准方法分离CBD,例如,包括收集植物材料和提取和纯化。
或者,CBD可以通过合成方法制备。
本发明的方法和用途
根据一个具体实施方案,提供了CBD或其组合物,用于预防和/或治疗由铜绿假单胞菌引起的疾病。
在一个具体实施方案中,所提供的CBD或其组合物可用作铜绿假单胞菌细菌的抑制剂。
在一个具体实施方案中,所提供的CBD或其组合物可用作铜绿假单胞菌细菌生物膜形成的抑制剂。
在一个更具体的实施方案中,所提供的CBD或其组合物可用于抑制或降低铜绿假单胞菌的毒力。
在另一个具体实施方案中,所提供的CBD或其组合物可用作群体感应的抑制剂,特别是毒力因子的产生。
另一个具体实施方案提供了CBD或其组合物,其用于预防和/或治疗由铜绿假单胞菌引起的医院获得性感染。
另一个实施方案提供了CBD或其组合物,其用于预防和/或治疗囊性纤维化患者中由铜绿假单胞菌引起的呼吸道感染。
另一个实施方案提供了CBD或其组合物,其用于预防和/或治疗烧伤患者中由铜绿假单胞菌引起的感染。
另一个实施方案提供了CBD或其组合物,其用于预防和/或治疗慢性伤口患者中由铜绿假单胞菌引起的感染。
在一个具体实施方案中,提供了CBD或其组合物用于保护艺术作品如绘画和古董手稿的用途。
在一个具体实施方案中,提供了CBD或其组合物用于预防人或兽医用途的制剂中铜绿假单胞菌污染的用途,例如化妆品、食品、饮料或药物制剂或用于去污的那些。在一个更具体的实施方案中,提供了CBD或其组合物作为灭菌和/或去污剂的用途。
在一个具体实施方案中,提供了CBD或其组合物用于对医学材料,用于医学、美容或卫生操作的房间或用于人或兽医用途的制剂进行灭菌和/或净化的用途,特别是用于净化或防止所述医用材料或制剂免受铜绿假单胞菌污染。
在一个具体实施方案中,CBD或其组合物用于预防食物污染或食物净化方面。
在一个具体实施方案中,CBD或其组合物用于防止水污染或水净化方面。
在一个具体实施方案中,在一个具体实施方案中,CBD或其组合物用于预防污染或用于医疗材料的净化,和/或用于医学、美容或卫生实践的房间,例如医疗/医院房间和/或洁净室。
在一个具体实施方案中,本发明的CBD或其组合物或试剂盒可用于本发明的方法,特别是抑制细菌毒力的方法和/或抑制生物膜形成的方法和/或预防和/或治疗由铜绿假单胞菌引起的疾病的方法,所述疾病选自下组:由医院获得性感染、呼吸道感染、皮肤和软组织感染或疾病、慢性伤口感染、慢性伤口感染、***、耳部感染、眼部感染、菌血症、败血症、中枢神经***感染和心内膜炎,所述方法包括给予有需要的受试者治疗有效量的CBD或其组合物。
在一个具体实施方案中,提供了一种用于保护艺术作品的方法,例如绘画和古董手稿,包括使所述艺术作品与CBD或其组合物接触的步骤。
在一个具体实施方案中,提供了一种预防铜绿假单胞菌污染/保存用于人或兽医用途的制剂的方法,例如食品制剂、饮料、培养或增溶培养基、化妆品或药物制剂或那些所述制剂的去污,包括使所述制剂与CBD或其组合物接触的步骤,特别是浓度为约0.1μg/mL至200mg/mL,例如约0.1μg/mL至1mg/mL,具体是0.1μg/mL至50μg/mL,更具体是1μg/mL至50μg/mL的CBD或其组合物。
在一个具体实施方案中,提供了食品或膳食制品的保存或净化方法。
在一个具体实施方案中,提供了一种保存或净化饮料或水的方法。
在一个具体实施方案中,提供了一种预防用于人或兽医的材料或房间的铜绿假单胞菌污染的方法,例如医用材料或对其进行去污/消毒的方法,所述方法包括使所述制剂与CBD或其组合物接触的步骤,特别是浓度为约0.1μg/mL至200mg/mL,例如约0.1μg/mL至1mg/mL,具体是0.1μg/mL至50μg/mL,更具体是1μg/mL至50μg/mL的CBD或其组合物。
根据一个具体实施方案,CBD或其组合物特别适用于本发明方法的医用材料的灭菌和/或净化。
根据一个具体实施方案,CBD或其组合物特别适用于用于医疗、美容或卫生实践的房间的消毒和/或净化,例如医疗/医院室和/或洁净室。
本发明的组合物
本发明的组合物或制剂可以作为药物制剂施用。
根据另一个实施例,本发明的组合物或制剂是包含CBD和至少一种其他生理学上可接受的载体、稀释剂或赋形剂的去污组合物。
本发明的药物组合物还可包含一种或多种药学上可接受的其他成分,例如明矾、稳定剂、抗微生物剂、缓冲剂、着色剂、调味剂、佐剂等。
本发明的组合物及其单位剂型和可以用作固体形式,例如片剂或填充胶囊,或液体如溶液、悬浮液、乳液、酏剂或含有它们的胶囊,全部用于口服,或以无菌注射溶液的形式用于肠胃外(包括皮下)使用。此类药物组合物及其单位剂型可包含常规比例的成分,有或没有其他活性化合物或原理,这些单位剂型可含有任何合适的有效量的活性成分,与所用的预期每日剂量范围相当。根据一个方面,本发明的组合物在呼吸道感染的情况下是可喷雾的或可吸入的,并且在泌尿感染的情况下是局部适用的溶液。
本发明的组合物也可以是液体制剂,包括但不限于水性或油性悬浮液、溶液、乳液、糖浆和酏剂。适于口服给药的液体形式可包括含有缓冲剂、悬浮剂和分散剂、着色剂、调味剂等的合适的水性或非水性载体。该组合物还可以配制成干燥产品,用于在使用前用水或其它合适的载体重构。这些液体制剂可含有添加剂,包括但不限于悬浮剂、乳化剂、非水性载体和防腐剂。悬浮剂包括但不限于山梨糖醇糖浆、甲基纤维素、葡萄糖/糖浆、明胶、羟乙基纤维素、羧甲基纤维素、硬脂酸铝凝胶和氢化食用脂肪。乳化剂包括但不限于卵磷脂、脱水山梨糖醇单油酸酯和***胶。非水性载体包括但不限于食用油、杏仁油、分馏椰子油、油性酯、丙二醇和乙醇。防腐剂包括但不限于对羟基苯甲酸甲酯或丙酯和山梨酸。
本发明的固体组合物可以是以常规方式配制的片剂或锭剂的形式。例如,用于口服给药的片剂和胶囊可含有常规赋形剂,包括但不限于粘合剂、填充剂、润滑剂、崩解剂和润湿剂。粘合剂包括但不限于糖浆、***胶、明胶、山梨糖醇、黄蓍胶、淀粉粘液和聚乙烯吡咯烷酮。填充剂包括但不限于乳糖、糖、微晶纤维素、玉米淀粉、磷酸钙和山梨糖醇。润滑剂包括但不限于硬脂酸镁、硬脂酸、滑石、聚乙二醇和二氧化硅。崩解剂包括但不限于马铃薯淀粉和淀粉乙醇酸钠。润湿剂包括但不限于十二烷基硫酸钠。可根据本领域熟知的方法包衣片剂。
可注射组合物通常基于可注射的无菌盐水或磷酸盐缓冲盐水或本领域已知的其他可注射载体。
本发明的组合物还可以配制成栓剂,其可以含有栓剂基质,包括但不限于可可脂或甘油酯。本发明的组合物还可以配制用于吸入,其可以是包括但不限于溶液、悬浮液或乳液的形式,其可以作为干粉或使用推进剂以气溶胶的形式给药,如二氯二氟甲烷或三氯氟甲烷。本发明的组合物还可以是配制的透皮制剂,其包含水性或非水性载体,包括但不限于乳膏、软膏、洗剂、糊剂、药膏、贴剂或膜。
本发明的组合物还可以配制用于肠胃外给药,包括但不限于注射或连续输注。用于注射的制剂可以是油性或水性载体中的悬浮液、溶液或乳液的形式,并且可以含有制剂,包括但不限于悬浮剂、稳定剂和分散剂。该组合物还可以粉末形式提供,用合适的载体重构,包括但不限于灭菌、无热原水。
本发明的组合物还可以配制成长效制剂,其可以通过植入或通过肌内注射给药。该组合物可以用合适的聚合或疏水材料(例如在可接受的油中的乳液),离子交换树脂或微溶衍生物(例如微溶盐)配制。
本发明的组合物也可以配制成脂质体制剂。脂质体制剂可包含脂质体,其穿透目标细胞或角质层,并与细胞膜融合,导致脂质体内容物进入细胞。其他合适的制剂可以使用类脂质体。类脂质体是类似于脂质体的脂质囊泡,膜主要由非离子脂质组成,其中一些形式有效地将化合物运输穿过角质层。
本发明化合物还可以以持续释放形式或从持续释放药物递送***给药。代表性持续释放材料的描述也可以在雷明顿药物科学的材料中找到。
或者,本发明的组合物也可以配制成气溶胶溶液或可吸入的药学上可接受的组合物,例如,适用于预防和/或治疗由革兰氏阴性细菌引起的肺部细菌感染。在这样的制剂中,CBD被制备成例如可吸入的干粉或作为气溶胶溶液。
本发明的组合物与常规使用的佐剂、载体、稀释剂或赋形剂一起可以以药物组合物和其单位剂型的形式放置,并且可以用作固体这种形式,例如片剂或填充胶囊,或液体,例如溶液、悬浮液、乳液、酏剂或含有它们的胶囊,全部用于口服使用,或者以无菌注射溶液的形式用于通过注射或连续输注肠胃外使用,或以乳膏、软膏、凝胶、糊剂或粉末的形式局部使用。
根据一个具体实施方案,本发明的组合物是兽医用组合物。
根据一个具体实施方案,本发明的组合物是洗手液,特别是用于医务人员的洗手液。
根据本发明的一个方面,本发明的制剂可以与制品相关联或整合在制品内,当制品置于合适的身体部位或适当的体腔中时,可以实现组合物的延时释放和/或机械释放。
根据本发明的另一方面,将CBD或其组合物涂覆在制品,特别是用于医疗,美容或卫生实践或与用于人或兽医用途的制剂接触的制品的表面上。根据另一方面,本发明的用于预防铜绿假单胞菌感染或病症的用途和方法,包括通过包含CBD的组合物涂覆用于保健,特别是重症监护和外科手术中使用的装置和材料(例如纺织品、手术材料、管道、呼吸机等......)的步骤。通常,将包含CBD的组合物掺入表面或喷涂到保健,特别是重症监护和外科手术中使用的所述装置和材料的表面上。其他材料以及配方加工技术等在雷明顿的“药学的科学与实践”第5部分中列出,2012年第22版,费城科技大学,Lippincott Williams和Wilkins,其通过引用并入本文。
组合
根据本发明,本发明的化合物和组合物及其药物制剂可以单独给药或与至少一种可用于防止污染或去污的助剂组合给药。
根据一个具体方面,本发明的助剂包括抗菌化合物和抗生素。
根据本发明,本发明的化合物和组合物、以及与所述助剂同时施用的药物制剂可以在相同或不同的组合物中和通过相同或不同的途径给药。
施用方式
本发明的组合物可以以任何方式施用,包括但不限于,口服、肠胃外、透皮、经粘膜、局部、通过吸入、通过口腔或鼻内或膀胱内给药,或其组合。
肠胃外给药包括但不限于静脉内、动脉内、腹膜内、皮下、肌内和心内。
本发明的组合物还可以局部给予皮肤、耳朵和眼睛。
本发明的组合物可以全身或局部给药。
本发明的组合物还可以以植入物的形式给药,其允许化合物及其制剂的缓慢释放以及缓慢控制,如静脉注射输液。
本发明的组合物可以作为单次或重复给药给予有需要的受试者。
本发明的组合物可以在之前给予有需要的受试者,与其他治疗方案同时或顺序进行。
作为单剂量或多剂量给予个体的剂量将根据多种因素而变化,包括药代动力学特性、患者病情和特征(性别、年龄、体重、健康、体型)、症状程度、同时治疗、治疗频率和所需效果。
患者
在一个实施方案中,本发明的患者是被铜绿假单胞菌感染或有被铜绿假单胞菌感染的风险的受试者。
诱发铜绿假单胞菌的易感因素包括宿主免疫力下降和先前使用广谱抗生素治疗。
在一个实施方案中,本发明的患者是微生物群改变的受试者。
在一个实施方案中,本发明的患者是免疫抑制的受试者。
在另一个实施方案中,本发明的患者是患有疾病或有患病风险的患者,所述疾病选自医院获得性感染、呼吸道感染、皮肤和软组织感染、伤口感染、牙齿和颊部感染、耳鼻喉科感染、泌尿***和/或***道感染、胃肠道感染、胆道感染、眼部感染、菌血症、败血症、中枢神经***感染和心内膜炎。
在更具体的实施方案中,本发明的患者是患有铜绿假单胞菌引起的呼吸道感染或有患其风险的患者,如囊性纤维化患者。
在另一个实施方案中,本发明的患者是有伤口的患者。
在另一个实施方案中,本发明的患者是烧伤患者。
在另一个实施方案中,本发明的患者是患有异物植入物和/或导管的患者或将接受体内植入或导管手术的患者。
在一个实施方案中,本发明的患者是具有抗生素抗性细菌引起的感染风险的受试者,所述抗生素用于动物育种。
试剂盒
根据一个方面,本发明涉及用于实施本发明的方法的试剂盒。
根据本发明的另一方面,提供了一种用于去污的试剂盒,特别是用于材料表面或制剂的净化,其包含CBD、本发明的组合物、以及任选的使用说明书。
根据另一个实施方案,本发明的试剂盒还包含至少一种抗菌化合物。
根据另一个实施方案,本发明的试剂盒还包含至少一种抗毒力因子试剂。
根据另一个实施方案,本发明的试剂盒包含一组或多组容器,其中每组单独使用的容器包括:第一容器,其包含冻干形式的CBD或液体制剂,和第二容器,其包含用于去污的消毒工具。
根据一个具体方面,本发明的制剂、试剂盒和方法可用于保护艺术品、化妆品、食品或饮料制备物去污/保存或医疗材料或房间清洁或去污的领域。
本文引用的参考文献通过引用整体并入本文。本发明的范围不受本文所述的具体实施方案和附图的限制,这些实施方案和附图旨在作为本发明各个方面的单一说明,并且功能上等同的方法和组件也在本发明的范围内。
实施例
以下缩写分别指下面的定义:
CBD(***二酚);CV(结晶紫);lasB(编码LasB弹性蛋白酶的基因);lasI(编码C12自诱导剂合成酶的基因);OD600(在600nm波长下测量的光密度);pqsH(参与喹诺酮自诱导剂合成的基因);rhlA(参与鼠李糖脂合成的基因);rhlI(编码C4自诱导剂合成酶的基因);wt(野生型)。
实施例1:通过CBD减少铜绿假单胞菌的生物膜形成
如下所述评估CBD对铜绿假单胞菌生物膜形成的影响。
将铜绿假单胞菌ATCC 27853菌株的过夜预培养物在2ml LB(溶原性发酵液)培养基中稀释至OD600(在600nm波长下测量的光密度)为0.1至聚丙烯管中。将含有浓度为1.9μg/ml,3.9μg/ml,7.8μg/ml,15.63μg/ml,31.25μg/ml,62.5μg/ml和125μg/ml的细菌和CBD的管在37℃温育12小时,不振荡。通过用蒸馏水洗涤一次除去浮游细胞,并用结晶紫(CV,1%水溶液)染色生物膜30分钟。丢弃CV并用水冲洗管两次以除去过量的染料。将染色的生物膜重新悬浮在33%乙酸中,并通过测定针对细菌密度标准化的悬浮液的OD600来估计它们的密度。
在CBD存在下测定铜绿假单胞菌ATCC 27853的生物膜形成显示,与没有CBD的对照相比,浓度在1.9μg/ml至31.25μg/ml之间的CBD可以减少约2倍的生物膜形成。
在较高的CBD浓度下,由于CBD在培养基中的溶解度降低,对生物膜形成的抑制作用降低。
实施例2:CBD诱导的铜绿假单胞菌毒力因子产生的减少
通过测量弹性蛋白酶酶活性来评估CBD对铜绿假单胞菌产生弹性蛋白酶的影响,铜绿假单胞菌是一种毒力因子,其表达受群体感应***的直接调节。
在两种细菌菌株中测定弹性蛋白酶产生:铜绿假单胞菌PAOW1(PT5)是一种野生型(wt),铜绿假单胞菌ΔlasIΔrhlI是群体感应信号传导的突变体,由于群体感应***的抑制而减少了弹性蛋白酶的产生/表达。将100μl过夜培养物的过滤的细菌上清液(含或不含500μg/ml的CBD,振荡培养物以使CBD更好的分散)加入到900μl的弹性蛋白刚果红(ECR)缓冲液(100mM Tris,1mM CaCl2,pH 7.5,含有20mg弹性蛋白ECR)中,然后在37℃振荡温育3小时。通过离心除去不溶性ECR,并在495nm处测量上清液的吸收,并根据细胞密度标准化。
在存在CBD的情况下,由铜绿假单胞菌PAOW1(PT5)产生的弹性蛋白酶的酶活性显示,与对照值相比,浓度为500μg/ml的CBD可使弹性蛋白酶的产生减少约30%(图1)。与对照(由wt制备弹性蛋白酶)相比,铜绿假单胞菌ΔlasIΔrhlI产生的弹性蛋白酶减少了约93%。
这些结果表明CBD可以有效地减少参与群体感应***的至少一些铜绿假单胞菌毒力因子的产生。
实施例3:CBD诱导的参与铜绿假单胞菌群体感应的基因表达的调节
通过与群体感应相关的基因的表达来评估CBD对铜绿假单胞菌群体感应***的影响。
将铜绿假单胞菌PAOW1(PT5)(wt)的过夜预培养物稀释至OD600为0.05,并在37℃下在含或不含500μg/ml的CBD中生长6小时。将0.5ml培养物加入1ml RNA保护细菌溶液中,用RNeasy柱(Qiagen)分离总RNA。用20单位的无RQ1 RNase的DNA酶(promega)通过DNA酶处理消除残留的DNA。通过苯酚/氯仿萃取和沉淀除去DNase后,用随机六聚体引物和Improm-II逆转录酶(promega)逆转录500ng RNA。用适用于CFX(4472942)的Sybr Select Master Mix(Thermofisher)通过实时PCR(qPCR)定量2.5μl10倍稀释的cDNA。引物,起始基因(bp)和所用的扩增子大小(bp)列于表1中。通过相应cDNA(互补DNA)的内标(oprF)值对每个扩增进行标准化。结果表示,与没有CBD培养的wt相比,倍数增加。测定了以下基因的表达:编码C4自诱导剂合成酶的rhlI;rhlA是参与鼠李糖脂合成的基因,编码C12自诱导剂合成酶的lasI,编码LasB弹性蛋白酶的lasB,pqsH是参与喹诺酮自诱导剂合成的基因。
表1
与对照条件相比,在CBD(500μg/ml)存在下孵育的铜绿假单胞菌PAOW1(PT5)基因表达的倍数诱导为:rhlI为1.46,rhlA为0.72,lasI为0.89,pqsH为0.53(图2),这表明CBD能够通过干扰群体感应***来影响铜绿假单胞菌的毒力。
序列表
rhlI引物309的核酸序列
SEQ ID NO:1:CTCTCTGAATCGCTGGAAGG
rhlI引物310的核酸序列
SEQ ID NO:2:GACGTCCTTGAGCAGGTAGG
rhlA引物的核酸序列299
SEQ ID NO:3:CGAGGTCAATCACCTGGTCT
rhlA引物300的核酸序列
SEQ ID NO:4:GACGGTCTCGTTGAGCAGAT
lasI引物的核酸序列311
SEQ ID NO:5:CTACAGCCTGCAGAACGACA
lasI引物312的核酸序列
SEQ ID NO:6:ATCTGGGTCTTGGCATTGAG
lasB引物301的核酸序列
SEQ ID NO:7:AAGCCATCACCGAAGTCAAG
lasB引物302的核酸序列
SEQ ID NO:8:GTAGACCAGTTGGGCGATGT
pqsH引物303的核酸序列
SEQ ID NO:9:ATGTCTACGCGACCCTGAAG
pqsH引物304的核酸序列
SEQ ID NO:10:AACTCCTCGAGGTCGTTGTG
Claims (25)
1.***二酚(CBD)或其组合物在制备用于预防和/或治疗由铜绿假单胞菌引起的疾病或病症的药物中的用途。
2.如权利要求1所述的CBD或其组合物的用途,其中所述疾病或病症选自由以下组成的组:医院获得性感染、呼吸道感染、皮肤和软组织感染、伤口感染、牙齿和颊部感染、耳鼻喉科感染、泌尿和/或***道感染、胃肠道感染、胆道感染、眼部感染、菌血症、败血症、中枢神经***感染和心内膜炎。
3.CBD或其组合物用于防止医疗材料、房间或制剂免受铜绿假单胞菌污染的用途,其特征在于,针对铜绿假单胞菌进行灭菌和/或净化,所述房间用于医疗、美容或卫生操作,所述制剂用于人或兽医用。
4.如权利要求3所述的CBD或其组合物的用途,其中所述制剂选自化妆品制剂和食品。
5.如权利要求3所述的CBD或其组合物的用途,其中所述制剂选自膳食制剂和饮料。
6.如权利要求3所述的CBD或其组合物的用途,其特征在于,作为医院或洁净室的消毒和/或去污剂。
7.如权利要求3所述的CBD或其组合物的用途,其特征在于,作为医疗材料的灭菌和/或去污剂。
8.CBD或其组合物用于保护艺术品免受铜绿假单胞菌污染的用途。
9.一种去污或灭菌组合物在制备用于杀灭铜绿假单胞菌的药物中的用途,其特征在于,所述去污或灭菌组合物包含浓度为0.1μg/mL至200mg/mL的CBD以及另外的生理学上可接受的载体或赋形剂。
10.根据权利要求9所述的用途,其特征在于,所述赋形剂包含稀释剂。
11.根据权利要求9所述的用途,其特征在于,所述去污或灭菌组合物包含浓度为0.1μg/mL至1mg/mL的CBD。
12.CBD或其组合物作为食品或化妆品制剂的防腐剂或灭菌剂用于杀灭铜绿假单胞菌的用途,其特征在于,CBD或其组合物的浓度为0.1μg/mL至200mg/mL。
13.根据权利要求12所述的用途,其特征在于,所述食品为饮料。
14.根据权利要求12所述的用途,其特征在于,CBD或其组合物的浓度为0.1μg/mL至1毫克/毫升。
15.CBD或其组合物在制备用于使材料表面或溶液免受铜绿假单胞菌污染的去污或灭菌的试剂盒中的用途,其特征在于,所述试剂盒包含CBD或其组合物,以及任选的使用说明书。
16.如权利要求15所述的用途,其中CBD的浓度为0.1μg/mL至200mg/mL。
17.如权利要求15所述的用途,其中CBD的浓度为0.1μg/mL至1mg/mL。
18.一种对医疗材料、房间或制剂进行灭菌和/或净化以使其免受灭铜绿假单胞菌污染的方法,其特征在于,包括使所述材料、房间或制剂与CBD或其组合物接触的步骤,所述房间用于医疗、美容或卫生操作,所述制剂用于人或兽医用。
19.一种通过使用CBD或其组合物抑制铜绿假单胞菌的细菌毒力和/或生物膜形成的离体方法,所述方法包括使含有所述细菌和/或其生物膜的材料或溶液与CBD或其组合物接触的步骤。
20.如权利要求19所述的方法,其中CBD组合物包含浓度为0.1μg/mL至200mg/mL的CBD以及另外的生理学上可接受的载体或赋形剂。
21.如权利要求20所述的方法,其中所述赋形剂包含稀释剂。
22.一种用于保护艺术作品免受铜绿假单胞菌污染的方法,其特征在于,包括使所述艺术品与CBD或其组合物接触的步骤。
23.如权利要求22所述的方法,其中所述艺术作品为绘画和古董手稿。
24.如权利要求22所述的方法,其特征在于,CBD组合物包含浓度为0.1μg/mL至200mg/mL的CBD以及另外的生理学上可接受的载体或赋形剂。
25.如权利要求24所述的方法,其特征在于,所述赋形剂包含稀释剂。
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AU2017272795A1 (en) | 2018-12-20 |
CL2018003425A1 (es) | 2019-01-18 |
RU2018146644A3 (zh) | 2020-07-30 |
CN109640977A (zh) | 2019-04-16 |
EP3942932A1 (en) | 2022-01-26 |
AU2017272795C1 (en) | 2023-06-08 |
RU2021127368A (ru) | 2021-10-15 |
WO2017207730A1 (en) | 2017-12-07 |
ES2897948T3 (es) | 2022-03-03 |
RU2018146644A (ru) | 2020-07-09 |
MX2018014845A (es) | 2019-05-06 |
CN114452282A (zh) | 2022-05-10 |
CL2020001312A1 (es) | 2020-08-21 |
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