CN101801521B - 生物膜中细菌细胞内的生理学分散响应诱导 - Google Patents
生物膜中细菌细胞内的生理学分散响应诱导 Download PDFInfo
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Abstract
本发明的一个方面涉及组合物。该组合物包括分散诱导剂,该分散诱导剂包含:H3C-(CH2)n-CHm CHmR,其中是碳-碳单键或双键,m是1或2,n是2-15,且R是羧酸、盐、酯或酰胺,其中酯或酰胺是羧酸的电子等排体或生物等排体。该组合物还包含添加剂组分,该添加剂组分选自以下组分中的一种或多种:生物杀灭剂、表面活性剂、抗生素、防腐剂、去污剂、螯合剂、毒力因子抑制剂、凝胶、聚合物、糊、可食用产物和可咀嚼产物。将该组合物配制成使其当与由微生物产生的生物膜接触时,其中该生物膜在表面上包含基质和微生物,该分散诱导剂选择性地作用于微生物并具有合适的生物反应,而不需要对所述基质直接作用,以将该生物膜分散。本发明也涉及使用该化合物的方法。
Description
本申请要求2007年5月14日提交的美国临时专利申请序号60/917,791和2008年1月2日提交的61/018,639的权益,这两个专利申请均通过引用而整体结合到本文中。
本发明在由NIH和NSF给予的授予编号为NSFMCB-0321672和NIH R15AI055521-01的政府资助下完成。因此本发明中政府拥有某些权利。
发明领域
本发明涉及在生物膜中诱导细菌细胞内的生理学分散响应的方法。
发明背景
由于生物膜结构的致密性质、生物膜细菌的假定的复位的生理状态和由生物膜基质聚合物给予的保护,天然和人造化学试剂不能充分地攻击和破坏有传染性的生物膜群体(Costerton等,″在自然界和疾病中的细菌生物膜″,Annu.Rev.Microbiol.41:435-464(1987);Hoiby等,″对细菌生物膜的免疫反应″,In Microbial Biofilms,Lappin-Scott等编辑,Cambridge:Cambridge University Press(1995))。增强的抗生素抗性是与生物膜细菌有关的一般特征。当粘附时,细菌显示极强的抗性,使生物膜细胞对各种抗微生物药物的敏感度比悬浮(自由漂浮)培养生长的同样细菌低10-1000倍。例如,被认为是最有效的抗菌剂之一的氧化性生物杀灭剂-氯(作为次氯酸钠),已经显示当与同种悬浮细胞比较时,杀灭金黄色葡萄球菌(Staphylococcus aureus)的生物膜细胞的浓度需要增加600倍(Luppens等,″评估金黄色葡萄球菌(Staphylococcus aureus)生物膜细胞对消毒剂的抗性的标准试验的开发″,Appl Environ Microbiol.68:4194-200(2002))。已经提出了解释生物膜细菌对抗生素的非常抗性的几种假设,包括:(i)减慢生物膜细菌(尤其是深入生物膜内的那些细菌)显示的代谢和***速率;(ii)生物膜EPS基质可用作吸附剂或反应物,减少可利用与生物膜细胞相互作用的试剂的量。此外,生物膜结构可通过阻挡进入生物膜区域而在物理上减少抗微生物药物的渗透;(iii)生物膜细胞在生理上与悬浮细菌不同,表达特异性的保护因子例如多药物外排泵和应力响应调节子(Brown等,″细菌生物膜对抗生素的抗性:生长速率相关的效应?″J.Antimicrob.Chemotherapy 22:777-783(1988);Anwar等,″老化生物膜的建立:细菌抵抗抗菌治疗的可能机制″,Antimicrob.AgentsChemother.36:1347-1351(1992);Mah等,″生物膜对抗微生物药物抗性的机制″,Trends Microbiol.9:34-39(2001);Sauer等,″铜绿假单胞菌(Pseudomonas aeruginosa)在发育期间显示多个表型作为生物膜″,J.Bacteriol.184:1140-1154(2002);Stewart,P.S.,″细菌生物膜的抗生素抗药机制″,Int.J.Med.Microbiol.292:107-113(2002);Donlan等,″生物膜:临床相关微生物的存活机制″,Clinical Microbiol.Reviews 15:167-193(2002);Gilbert等,″微生物生物膜群落的生理和集体对抗″,Adv.Microb.Physiol.46:202-256(2002);Gilbert等,″体外和体内的生物膜:单一机制暗示交叉抗药吗?″J.Appl.Microbiol.Suppl.98S-110S(2002))。如详细的分子研究所显示的,显然这些因子中的每一个在生物膜对抗微生物药物的不寻常的抗药中起作用。初始治疗通常对仅在生物膜微集落的边缘杀灭细菌有效。深陷于这些微集落中的细菌不受抗生素影响并形成连续传播感染的胞窝。
由于它们对抗有效的治疗,因此在感染中和在工业***中微生物生物膜存在显著的问题。
分离是用于描述细胞(单个地或成组地)从生物膜或基质去除的一般性术语。Bryers,J.D.,″模拟生物膜积聚″,在:PhysiologyModels in Microbiology。Bazin等编辑,Boca Raton,FL.,第2卷,第109-144页(1988)分成细菌从生物膜分离的四种不同分离机制。它们是:磨损、轻檫、侵蚀和蜕落。已经主要从作用于生物膜细菌的化学和物理环境的观点来描述这些机制。许多作者已经暗示活性分离作为生理学上调节的事件,但很少进行研究以显示细菌从生物膜分离的生物学基础。
由Peyton等,″微生物生物膜和生物膜反应器″,BioprocessTechnol.20:187-231(1995)对铜绿假单胞菌(P.aeruginosa)进行了对分离的生理调节的一项研究。在他们的研究工作中,观察到底物限制致使分离速率降低,大概降低生长速率的结果。Allison等,″胞外产物作为荧光假单胞菌(Pseudomonas fluorescens)生物膜形成和分离的介体″,FEMS Microbiol.Lett.167:179-184(1998)显示,在延长的温育之后,荧光假单胞菌(P.fluorescens)生物膜进行分离,同时EPS减少。在热纤维梭菌(Clostridium thermocellum)中,稳定期的发病已经与增强从基质分离有关(Lamed等,″经过广泛的表面细胞器在热纤维梭菌(Clostridium thermocellum)中接触和分解纤维素(Cellulolysis)″,Experientia 42:72-73(1986))。已经假定饥饿可通过未知的机制导致分离,允许细菌寻找更富于营养素的栖息地(O′Toole等,″当微生物发育时形成生物膜″,Ann.Rev.Microbiol.54:49-79(2000))。
许多实验室已经观察到从流动***转变成分批培养***导致生物膜分离。一个实验室已经观察到,当在连续培养***中停止流动时铜绿假单胞菌(P.aeruginosa)的生物膜细胞的可重复的分离(Davies,D.G.,″在生物膜形成和分散中基质聚合物的调节″,在Microbial Extracellular Polymeric Substances,第93-112页,Wingender等编辑,Berlin:Springer(1999))。
其它的已经提出降解酶的释放。用其30产生表面蛋白释放酶(SPRE)的革兰氏阳性生物体变形链球菌(Streptococcus mutans)发现了一个这样的实例,显示介导从细胞被膜释放蛋白质(Lee等,″变形链球菌(Streptococcus mutans)生物膜细胞通过内源性酶活性的分离″,Infect.Immun.64:1035-1038(1996))。Boyd等,″海藻酸裂解酶在铜绿假单胞菌(Pseudomonas aeruginosa)的细胞分离中的作用″,Appl Environ.Microbiol.60:2355-2359(1995)显示海藻酸裂解酶的过表达引起海藻酸盐的降解。当诱导铜绿假单胞菌(P.aeruginosa)的粘液型菌株过表达海藻酸裂解酶时,通过轻洗更容易的从固体培养基除去细胞。
细胞密度依赖性调节也可对酶的释放起作用,该酶可以降解生物膜基质聚合物,允许细菌从生物膜分散。在the Center for BiofilmEngineering at Montana State University,USA(Davies,D.G.和Costerton,J.W.)中和在University of Exeter,UK,Lapin-Scott博士的实验室中,已经观察到当某些细菌(包括铜绿假单胞菌(P.aeruginosa))在生物膜细胞簇中达到高细胞密度时,细菌经常经历分离事件。缺乏合成群体感应自体诱导剂3OC12-HSL的能力的铜绿假单胞菌(P.aeruginosa)突变体,在用温和的去污剂处理后对分离敏感(Davies等,″在细菌生物膜的发育中涉及细胞-细胞信号″,Science 280:295-298(1998))。其它研究者已经证明,高丝氨酸内酯可在分离中起作用。Lynch等,″在不锈钢上形成的嗜水气单胞菌(Aeromonas hydrohila)生物膜中群体感应的研究:In:Biofilms-The Good,the Bad and the Ugly,Wimpenny等编辑。Bioline,Cardiff,第209-223页(1999)报导了增强嗜水气单胞菌(Aeromonashydrophila)从生物膜的分离,和Puckas等,″在自由营生光合作用细菌球形红细菌(Rhodobacter sphaeroides)中的群体感应***″J.Bacteriol.179:7530-7537(1997)报导了高丝氨酸内酯的生成与在球形红细菌(Rhodobacter sphaeroides)中的细胞簇形成成负相关。
已经认识到铜绿假单胞菌(P.aeruginosa)生物膜在分批培养瓶中(在玻璃液体界面)不发育成宏观的生物膜结构。然而,当培养基连续地通过这样的烧瓶泵送时,(因为在恒化器中)放纵的生物膜发育完全覆盖玻璃表面。当在这样的***中停止流动时,生物膜在许多天一般约72小时之后脱落(Davies等,″在细菌生物膜的发育中涉及细胞-细胞信号″,Science 280:295-298(1998))。已经从大量革兰氏阴性细菌和***以及细菌的混合培养物观察到生物膜不能在分批培养中发育。该现象证明分批生长的一些方面抑制生物膜发育。
在生物膜发育的末期期间,细菌的蛋白质图比前期、表示成熟II的生物膜细菌更充分地匹配悬浮细胞的蛋白质图(见本申请的图3,和Sauer等,″铜绿假单胞菌(Pseudomonas aeruginosa)在作为生物膜发育期间显示多个表型″,J.Bacteriol.184:1140-1154(2002))。
由于生物膜结构的致密性质、生物膜细菌的假定降低的生理状态和生物膜基质聚合物给予的保护,目前天然和人造化学试剂不能充分地攻击和破坏有传染性的生物膜群体(Costerton等,″在自然界和疾病中的细菌生物膜″,Annu.Rev.Microbiol.41:435-464(1987);Hoiby等,″对细菌生物膜的免疫反应″,In Microbial Biofilms,Lappin-Scott等编辑,Cambridge:Cambridge University Press(1995))。
本发明涉及克服了本领域中这些和其他不足之处。
发明概述
本发明的一个方面涉及一种组合物。该组合物包含具有下式的一种或多种分散诱导剂:其中是碳-碳单键或双键,m是1或2,n是2-15,且R是羧酸、盐、酯或酰胺,其中酯或酰胺是羧酸的电子等排体或生物等排体(biostere)。该组合物还包含选自以下的一种或多种添加剂组分:生物杀灭剂、表面活性剂、抗生素、防腐剂、去污剂、螯合剂、毒力因子抑制剂、凝胶、聚合物、糊、可食用产物和可咀嚼产物。将所述组合物配制成使其当与由微生物产生的生物膜接触时,其中该生物膜在表面上包含基质和微生物,所述分散诱导剂不需要对基质直接作用,而选择性地作用于所述微生物并具有合适的生物反应,以将该生物膜分散。
本发明的另一个方面涉及一种治疗或预防受试者中由生物膜介导的病症的方法。该方法包括提供具有或易感生物膜介导的病症的受试者,该生物膜由微生物产生,因此生物膜在表面上包含基质和微生物。在有效的使分散诱导剂不需要对基质直接作用,而选择性地作用于所述微生物并具有合适的生物反应的条件下,将分散诱导剂给予受试者,该分散诱导剂包含:其中是碳-碳单键或双键,m是1或2,n是2-15,且R是羧酸、盐、酯或酰胺,其中酯或酰胺是羧酸的电子等排体或生物等排体。结果,治疗或预防了所述受试者中由生物膜介导的病症。
本发明的又一个方面涉及一种处理或抑制表面上生物膜形成的方法。该方法包括提供具有或易感生物膜形成的表面,该生物膜由微生物产生,其中该生物膜在表面上包含基质和微生物。在有效的使分散诱导剂不需要对基质直接作用,而选择性地作用于所述微生物并具有合适的生物反应的条件下,将分散诱导剂给予表面,该分散诱导剂包含:其中是碳-碳单键或双键,m是1或2,n是2-15,且R是羧酸、盐、酯或酰胺,其中酯或酰胺是羧酸的电子等排体或生物等排体。结果,处理或抑制了表面上生物膜的形成。
本申请的另一个方面涉及一种溶液,该溶液包含具有下式的分散诱导剂:其中是碳-碳单键或双键,m是1或2,n是4-7,且R是羧酸,其中所述诱导剂以小于0.5%重量的浓度存在,且其中所述溶液的pH大于5。
本发明的又一个方面涉及一种组合物,该组合物包含选自以下组分中一种或多种的组分:生物杀灭剂、表面活性剂、抗生素、防腐剂、去污剂、螯合剂、毒力因子抑制剂、凝胶、聚合物、糊、可食用产物和可咀嚼产物。此外,该组合物包括分散诱导剂,该分散诱导剂包含:其中是碳-碳单键或双键,m是1或2,n是4-7,且R是羧酸。将诱导剂配制成非盐形式。
本发明也涉及包括2-癸烯酸顺式异构体的溶液,其中该溶液选自皮肤软膏剂、牙膏和漱口剂,且其中该溶液基本上不含2-癸烯酸反式异构体。
本申请的另一种形式涉及包含2-癸烯酸顺式异构体的溶液,其中该溶液选自皮肤软膏剂、牙膏和漱口剂,且其中所述溶液不含反式异构体。
本申请的另一种形式是一种方法,该方法包括提供接触透镜和含浓度小于0.5%重量的分散诱导剂的溶液,所述诱导剂包含:其中是碳-碳单键或双键,m是1或2,n是4-7,且R是羧酸、盐、酯或酰胺,其中酯或酰胺是羧酸的电子等排体或生物等排体。然后用所述溶液处理接触透镜。
本发明的还一种形式是一种方法,该方法包括提供有皮肤病的受试者和pH大于5的溶液,其中所述溶液包含浓度小于0.5%重量的分散诱导剂,所述诱导剂包含:其中是碳-碳单键或双键,m是1或2,n是4-7,且R是羧酸、盐、酯或酰胺,其中酯或酰胺是羧酸的电子等排体或生物等排体。然后用该溶液治疗皮肤病。
本发明的又一些方面涉及一些方法,此类方法治疗烧伤的受试者;治疗和/或预防牙斑、龋齿、齿龈疾病和口腔感染;清洁和/或消毒接触透镜;在受试者的皮肤上治疗和/或预防痤疮或其它生物膜相关的皮肤感染和在受试者中治疗和/或预防慢性生物膜相关疾病。此类方法涉及在对分别完成各任务有效的条件下,给予本发明的分散诱导剂。生物膜分散诱导剂有利地对生物膜内的微生物具有高度的生物活性,因此,药学上可接受的制剂不必对破坏基质直接有化学或机械活性。因此,所述组合物可具有温和的pH,且是非刺激性的。
本发明也涉及一种组合物,该组合物包含一种或多种分散诱导剂和一种或多种添加剂组分。这些添加剂组分选自生物杀灭剂、表面活性剂、抗生素、防腐剂、去污剂、螯合剂、毒力因子抑制剂、凝胶、聚合物、糊、可食用产物和可咀嚼产物。将所述组合物配制成使其当与由微生物产生的生物膜接触时,其中该生物膜在表面上包含基质和微生物,所述分散诱导剂不需要直接作用,而选择性地作用于所述微生物并具有合适的生物反应,以使所述基质破坏。
本发明的另一个方面涉及一种治疗或预防受试者中由生物膜介导的病症的方法。该方法包括提供具有或易感生物膜介导的病症的受试者,该生物膜由微生物产生,因此生物膜在表面上包含基质和微生物。在有效的使分散诱导剂不需要对基质直接作用,而选择性地作用于所述微生物并具有合适的生物反应的条件下,将分散诱导剂给予受试者,因此治疗或预防了受试者中由生物膜介导的病症。
本申请的又一个实施方案涉及一种处理或抑制表面上生物膜形成的方法。这涉及提供具有或易感生物膜形成的表面,该生物膜由微生物产生,因此生物膜在表面上包含基质和微生物。在有效的使分散诱导剂不需要对基质直接作用,而选择性地作用于所述微生物并具有合适的生物反应的条件下,将分散诱导剂给予表面,因此处理或抑制了表面上生物膜形成。
本发明通过人工诱导细菌经过生物膜分散的生理学处理,来解决″生物膜问题″。诱导分散的能力将允许直接控制生物膜,并将改善已有的生物杀灭剂、局部抗生素、去污剂等处理。人工分散将有益的情况的实例包括改善的接触透镜和牙齿的清洁、在家中、在工业中和在医疗社区中提高的防腐剂活性和现有的抗生素治疗例如感染铜绿假单胞菌(Pseudomonas aeruginosa)的烧伤患者的抗生素治疗增强的杀灭活性。
附图简述
图1A-B是用抗生素和/或分散诱导剂处理生物膜的图示代表。如图1A所示,在处理之后,仅在生物膜表面上的细胞被抗生素杀灭。图1B是与抗生素处理一起诱导分散的生物膜的图示代表。分散的细胞在处理期间被完全杀灭。
图2A-C描绘添加氯仿提取的用过(spent)培养基(CSM)对铜绿假单胞菌(Pseudomonas aeruginosa)的成熟生物膜的影响,该用过培养基包含诱导分散的化合物。图2A显示在流动池中载玻片上按连续培养生长的生物膜。图2B显示在添加分散诱导剂之后5分钟生物膜的相同区域。图2C显示在用分散诱导剂初始处理30分钟之后生物膜的完全解聚。
图3A是生物膜生命周期的图示代表。1,悬浮细菌转移(主动和被动地)至基底膜。2,细胞表面分子与基底膜相互作用,导致可逆的表面附着。3,细菌细胞中的表型改变导致细胞表面修饰和细胞外聚合物质的产生,这使细胞不可逆地粘结至表面。4,随着生物膜成熟的发生,连续发生生理学变化,并且在代谢、细胞-细胞信号和形态学方面发生改变。5,随着生物膜分离的发生,细胞释放降解酶消化基质聚合物材料,并改变表面附属物。在图3B的底部显微照片系列按顺序显示铜绿假单胞菌(P.aeruginosa)生物膜发育第5期的相衬显微照片,该铜绿假单胞菌(P.aeruginosa)在流动池内按连续培养生长并通过显微镜成像。(Sauer等,″铜绿假单胞菌(Pseudomonas aeruginosa)在作为生物膜发育期间显示多个表型″,J.Bacteriol.184:1140-1154(2002),该文献通过引用而整体结合到本文中)。
图4A-B是由流动的停止诱导的生物膜20分散的相衬显微照片。图4A显示在流动条件下的早期生物膜发育,而图4B是在流动停止72小时之后同样的位置。
图5是显示氯仿提取对用过培养基分散活性影响的图。生物膜在生物膜管状反应器内的EPRI培养基中以连续培养方式培养6天(Sauer等,″铜绿假单胞菌(Pseudomonas aeruginosa)在作为生物膜发育期间显示多个表型″,J.Bacteriol.184:1140-1154(2002),该文献通过引用而整体结合到本文中),并用用过培养基(对照)和氯仿提取的用过培养基(CSM)处理。以在培养管末端收集的培养流出物的光密度,测定细胞分散。误差线代表3次重复实验的标准差。
图6A显示按证明是自然分散响应的连续培养生长的铜绿假单胞菌(P.aeruginosa)生物膜的微集落。在生物膜发育的分散期期间,细菌开始在细胞簇内能动并通过微集落壁中的裂口流出大量的液体。各显微照片显示其内部已经按该方式排空的微集落。箭头表示空隙的位置。放大1000倍摄取图像;柱表示10μm。图6B是透射光的图像,图6C是显示尺寸依赖于分散响应的荧光图像。具有大于40μm直径×10μm厚度尺寸的按连续培养生长的生物膜微集落显示分散(左3)。在该最小尺寸下的微集落仍然为″实心″(右2显微照片)。荧光指示细胞的存在(在染色体上的lacZ报道基因)。所有的图像均为放大500倍的同样的相对尺寸;柱表示40μm。箭头表示微集落内的空隙区域。
图7A-D显示用用过培养基、CSM和顺-2-癸烯酸处理铜绿假单胞菌(P.aeruginosa)成熟生物膜。如图7A中所示,在30min时,使在聚硅氧烷管中生长的生物膜暴露至用过培养基或新鲜培养基。连续收集流出物中的细菌100min,并通过OD600测定细胞密度。如图7B所示,使生物膜在聚硅氧烷管中按连续培养生长4天,并转换至新鲜培养基生长1hr,或转换至CSM生长1hr。对照管的挤出内容物显示完整的生物膜。CSM处理的生物膜的挤出内容物显示分散。如图7C中所示,显微照片显示将CSM添加至在显微镜安装的流动池中按连续培养生长的成熟生物膜。微集落解聚显示在7min开始。在暴露30min之后,微集落已经完全解聚。分散的细胞是主动能动的(在静态图像中不可见),表明与在完整微集落(在CSM添加前)中的细胞相比表型发生变化。如图7D所示,将10μM顺-2-癸烯酸(顺-DA)添加至在显微镜安装的流动池中按连续培养生长的成熟生物膜中。微集落解聚显示在11min开始。完全的微集落解聚显示在30min暴露时间内。用载液处理的对照生物膜处理长达1hr不受影响。
图8A-B显示在CSM连续存在下的生物膜发育,该CSM用改良的EPRI稀释至用过培养基的浓度。在CSM存在下生长的生物膜的平均厚度(图8A)和表面积(图8B)显著小于未处理的生物膜。灰色柱表示用CSM处理的生物膜。黑色柱表示在分散诱导剂存在下生长的生物膜。误差线代表20个随机选择的微集落的一个标准差。
图9显示使用微量滴定板分散生物测定法,不同细菌生物膜通过铜绿假单胞菌(P.aeruginosa)CSM的分散。Y轴表示在3次重复实验中,在用CSM或含载体对照(-)的无菌培养基处理1hr之后,释放至16个平行测定孔的批量液体内的细胞数。阴影线表示在载体对照样品中分散的水平。在通过Student T检验测定所示的P值下,CSM样品与对照之间的所有差异均在统计学上有显著性。
图10A-C显示微量滴定板分散生物测定。图10A显示从含生物膜的微量滴定板孔释放的细胞的光密度。白色柱表示用EPRI单独处理的对照样品。灰色柱表示用CSM处理的样品。黑色柱表示用CSM的C-18反相HPLC流份处理的生物膜,该HPLC用2%-75%的乙腈梯度洗脱。结果是16个平行测定孔的平均值,误差线表示一个标准差。CSM和22分钟HPLC样品的Student T检验结果显示P<0.001。图10B显示各种浓度的顺-2-癸烯酸与用过培养基比较的微量滴定板生物膜分散生物测定。从含生物膜的微量滴定板孔释放的细胞的光密度。阴性对照孔包含用10%乙醇/EPRI处理的铜绿假单胞菌(P.aeruginosa)。灰色柱表示用用过培养基处理的生物膜。黑色柱表示用增加顺-2-癸烯酸浓度的10%乙醇溶液处理的生物膜。结果是16个平行测定孔的平均值,误差线表示一个标准差。与对照比较,所有顺-2-癸烯酸样品的Student T检验显示P<0.001。图10C显示顺-2-癸烯酸的结构。
图11显示使用微量滴定板分散生物测定法,不同细菌生物膜通过顺-2-癸烯酸的分散。Y轴表示在用含0.01μM顺-2-癸烯酸(CDA)或载体对照(-)的培养基+10%乙醇处理1小时后,在3次重复的实验中,释放至16个平行测定孔的批量液体内的细胞数量。阴影线表示在载体对照样品中分散的水平。在通过Student T检验测定所示的P值下,在顺-2-癸烯酸处理的样品和对照之间的所有差异均具有统计学显著性。
图12A-C显示铜绿假单胞菌(P.aeruginosa)CSM和顺-2-癸烯酸的光谱分析。图12A显示171M/Z分子的产物离子质量峰,该分子在活性HPLC CSM流份中检测到,并用于合成顺-2-癸烯酸。Y轴表示强度;X轴表示阳离子模式的M/Z。CSM样品与合成顺-2-癸烯酸的峰匹配。注意在质谱中,峰强度不是浓度的直接指示。图12B显示铜绿假单胞菌(P.aeruginosa)CSM和顺-2-癸烯酸的GC-MS图谱。在15.9分钟的CSM样品峰表示溶剂载体。Y轴表示强度;X轴以分钟表示时间。图12C显示铜绿假单胞菌(P.aeruginosa)CSM和顺-2-癸烯酸的FT-IR图谱。Y轴表示吸收度;X轴表示厘米的倒数。
图13显示将10μM顺-2-癸烯酸(顺-DA)添加至成熟生物膜中,该生物膜在显微镜安装的流动池内按连续培养生长。微集落解聚显示在11分钟开始。在15分钟暴露时间内显示完全的微集落解聚。用载液处理的对照生物膜不受处理长达1小时的影响。
发明详述
本发明的一个方面涉及一种组合物。该组合物包括一种或多种分散诱导剂,该分散诱导剂包含:其中是碳-碳单键或双键,m是1或2,n是2-15,且R是羧酸、盐、酯或酰胺,其中酯或酰胺是羧酸的电子等排体或生物等排体。该组合物还包含选自以下的一种或多种添加剂组分:生物杀灭剂、表面活性剂、抗生素、防腐剂、去污剂、螯合剂、毒力因子抑制剂、凝胶、聚合物、糊、可食用产物和可咀嚼产物。将所述组合物配制成使其当与由微生物产生的生物膜接触时,其中该生物膜在表面上包含基质和微生物,所述分散诱导剂不需要对基质直接作用,而选择性地作用于所述微生物并具有合适的生物反应,以将该生物膜分散。在达到该结果中,本发明的分散诱导剂优选可以直接作用于基质。或者,分散诱导剂可以作用于微生物,这又用于破坏基质。该效果也可涉及不依赖于对基质直接作用。典型地,生物膜诱导剂对基质将没有直接作用或以对基质无直接作用的浓度存在是显然的。在另一方面,有效浓度的范围提出微生物内的生化反应机制,其中分散诱导剂模拟细胞间通讯组合物。该组合物用于通过细菌诱导分散响应,这又对细菌从生物膜释放起作用。此外,该组合物能够作用于不在生物膜内的细菌(悬浮细菌),包括具有防止生物膜形成的生理学反应的这些细菌。组合物的另外组分可涉及从表面或基体破坏或除去基质。例如,组合物可包含适合于从牙齿摩擦除去噬菌斑的洁齿剂。
以上诱导剂的R基团可选自:或者,R可以是高丝氨酸内酯或呋喃酮基团。所述组合物也包括添加剂组分,例如以下组分中的一种或多种:生物杀灭剂、表面活性剂、抗生素、防腐剂、去污剂、螯合剂、毒力因子抑制剂、凝胶、聚合物、糊、可食用产物或可咀嚼产物。
本发明的分散诱导剂期望包含7-10个碳原子。优选该诱导剂是羧酸(例如单不饱和脂肪酸)。更优选分散诱导剂包含:CH3-(CH2)n-CH=CHCOOH该分散诱导剂的合适的非盐形式分别是以下的顺式和反式异构体:其中,优选顺式异构体。
其它合适的链烷酸包括己酸、庚酸、辛酸、壬酸、癸酸、十一烷酸、十二烷酸、十三烷酸、十四烷酸、十五烷酸、十六烷酸、十七烷酸、十八烷酸和十九烷酸。
有用的链烯酸包括2-己烯酸、2-庚烯酸、2-辛烯酸、2-壬烯酸、2-十一碳烯酸、2-十二碳烯酸、2-十三碳烯酸、2-十四碳烯酸、2-十五碳烯酸、2-十六碳烯酸、2-十七碳烯酸、2-十八碳烯酸和2-十九碳烯酸。这些可以是顺式或反式异构体。
如下,本发明的组合物可以在许多的pH范围配制,以治疗不同类型的细菌:1.5-4.5用于嗜酸性细菌;4.5-8.0用于耐酸菌;6.8-7.4用于嗜基本上中性pH的细菌;和8.0-9.8用于耐碱菌。对于酸逆流受试者,基本上中性的pH尤其理想。分散诱导剂的浓度可以是0.01μM-30mM。
所述组合物可以完全或基本上(即小于10%重量)不含乙醇和/或不含甲醛。
本发明也包括用所述组合物涂布的表面(或基体)。
本发明的另一个方面涉及一种治疗或预防受试者中由生物膜介导的病症的方法。该方法包括提供具有或易感由生物膜介导的病症的受试者,该生物膜由微生物产生,因此该生物膜在表面上包含基质和微生物。在有效的使分散诱导剂不需要对基质直接作用,而选择性地作用于所述微生物并具有合适的生物反应的条件下,将分散诱导剂给予受试者,该分散诱导剂包含:其中是碳-碳单键或双键,m是1或2,n是2-15,且R是羧酸、盐、酯或酰胺,其中酯或酰胺是羧酸的电子等排体或生物等排体。结果,治疗或预防了在受试者中由生物膜介导的病症。将生物膜分散的方法还可包括与给予分散诱导剂联合,给予生物膜抗微生物处理。该处理可以是给予生物杀灭剂(例如过氧化氢)、表面活性剂、抗生素、防腐剂、去污剂、螯合剂、毒力因子抑制剂、凝胶、聚合物、糊、可食用产物、可咀嚼产物、超声波处理、放射处理、热处理和/或机械处理。
本发明的又一个方面涉及一种处理或抑制表面上生物膜形成的方法。该方法包括提供具有或易感生物膜形成的表面,该生物膜由微生物产生,其中该生物膜在表面上包含基质和微生物。在有效的使分散诱导剂不需要对基质直接作用,而选择性地作用于所述微生物并具有合适的生物反应的条件下,将分散诱导剂给予表面,该分散诱导剂包含:其中是碳-碳单键或双键,m是1或2,n是2-15,且R是羧酸、盐、酯或酰胺,其中酯或酰胺是羧酸的电子等排体或生物等排体。结果,处理或抑制了表面上生物膜的形成。
在一个实施方案中,待处理的表面包括留置医疗装置,例如导管、呼吸器和通风器。另外,表面可以在植入的医疗装置中,该植入的医疗装置包括支架、人工瓣膜、关节、钉、骨植入物、缝合线、U形钉、起搏器和其它临时性或永久性装置。本发明的分散诱导剂也可以包含在外科用胶中。在另一个实施方案中,待处理的表面包括***装置、桶状物、厨房用具、工作台面、淋浴帘、薄浆、盥洗室、工业食品和饮料生产设施、地板和食品加工设备。在还一个实施方案中,待处理的表面是热交换器表面或过滤器表面。因此,处理提供了降低热交换器或过滤器生物结垢程度的手段。在最终的实施方案中,待处理的表面是海上构筑物,包括船、桥墩、石油平台、水摄取口、筛网和观察口。表面或者可以与水处理和/或分配***(例如饮用水处理和/或分配***、池和矿泉水处理***、制造操作中的水处理和/或分配***和牙科水处理和/或分配***)相联系。表面也可以与石油钻探、贮藏、分离、精制和/或分配***(例如石油分离列车、石油容器、石油分配管和石油钻探设备)相联系。分散诱导剂也可以包括在一些制剂中,这些制剂针对减少或消除在多孔介质,例如负载油和气的地质构造的多孔介质中生物膜沉积或生物结垢。所述处理可通过将涂层例如漆涂覆至表面来完成。
在表面上抑制生物膜形成的方法还可包括与给予分散诱导剂联合给予表面抗微生物处理。可以给予以下的处理:生物杀灭剂、表面活性剂、抗生素、防腐剂、消毒剂、药物、去污剂、螯合剂、毒力因子抑制剂、超声波处理、放射处理、热处理和机械处理。在一个实施方案中,分散诱导剂和抗微生物处理同时给予。在另一个实施方案中,分散诱导剂和抗微生物处理分别给予。
为了抑制在表面上形成生物膜,可以将分散诱导剂浸渍在表面内。或者,分散诱导剂可以在涂布在表面上的共聚物或凝胶中。
本发明也涉及治疗烧伤受试者的方法。该方法包括在对治疗受试者的烧伤有效的条件下,给予本发明的分散诱导剂。本发明的具体应用提供用于烧伤患者的局部敷料,该局部敷料包含诱导分散的分子或其天然或合成类似物,以防止有传染性的生物膜发育,或分散已有有传染性的生物膜的细胞。
本发明还涉及在受试者中治疗和/或预防牙斑、龋齿、齿龈疾病、牙周病和口腔感染的方法。该方法包括用本发明的分散诱导剂处理受试者的口腔。可以用含分散诱导剂的洁齿剂、漱口剂、牙线、胶、条状物、牙膏、牙刷,和含分散诱导剂的其它制剂来进行处理。所述组合物也可包含通常添加至牙用组合物的在牙科领域中已知的其它化合物。例如,分散诱导剂组合物也可包括氟化物、脱敏剂、防牙垢剂、抗菌剂、再矿化剂、增白剂和抗龋剂。
分散诱导剂存在的量将根据包含分散诱导剂的牙用组合物而改变。已经发现分散诱导剂在宽的浓度范围内具有抗口腔细菌的活性。例如,分散诱导剂可以0.1nM-10mM的量存在。然而,可使用更低和更高的浓度,这取决于牙用组合物、存在于分散诱导剂组合物中的其它组分和本领域中的技术人员所认识到的各种其它因素。分散诱导剂的已知性质,例如其脂肪酸特性及其疏水性将协助熟练的技术人员决定应该使用多少分散诱导剂,决定化合物将如何与其它组分化学相互作用,并提供关于化合物的其它有用的信息。
本发明中考虑具体的牙科应用和牙用组合物。在这点上,本发明涉及包含分散诱导剂组合物的牙刷。如在本领域中所熟知的,牙刷包含许多刷毛和刷毛固定在其上的固体载体,其中固体载体包括具有许多接受刷毛的簇毛孔的刷头。在本领域中熟知基本牙刷的变化和改进。见例如美国专利第7,251,849号,该专利通过引用而整体结合到本文中。
本发明的分散诱导剂具有如上所述的化学式。上面也阐述了可包括于分散诱导剂组合物中的另外组分。可通过在本领域中已知的方法,将分散诱导剂组合物掺入牙刷的各种部件中。例如,分散诱导剂组合物可包含于牙刷的簇毛孔中。对于组合物如何可以包含在牙刷的簇毛孔内的实例,见美国专利第5,141,290号,该专利通过引用而整体结合到本文中。或者,分散诱导剂组合物可涂布或包埋在牙刷的刷毛内。
牙刷的其它部件也可涂布或包埋有分散诱导剂组合物,包括补充刷毛和设计与口腔接触的牙刷的任何部件。例如,牙刷通常包含橡胶桨、舌清洁器或用于与牙齿、舌、牙龈或口腔其它区域接触目的的从头部延伸的其它部件。这些部件可包埋有分散诱导剂组合物,和任选表面活性剂、生物杀灭剂和/或上述的其它添加剂。
为了有助于控制分散诱导剂从牙刷释放,分散诱导剂组合物可包含与分散诱导剂相互作用以有助于控制释放的试剂。该试剂可按取决于预定用途而加速或延长释放的方式,与分散诱导剂相互作用。控制释放的水平也可以取决于分散诱导剂如何容易或困难地粘附至其施加至的牙刷部分。在优选的实施方案中,分散诱导剂在反复的刷牙过程中从牙刷缓慢释放。本领域的技术人员熟知能够保证活性成分缓慢释放的试剂。
也可通过将分散诱导剂包封在允许控制释放的囊化***,来实现控制释放。在该实施方案中,分散诱导剂组合物优选为将分散诱导剂包封的许多小的微球形式。该微球可以具有可溶性材料的外部涂层,其确保分散诱导剂在反复刷的时间内能够缓慢释放。合适的微球包括在美国专利第5,061,106号中公开的那些,该专利通过引用而整体结合到本文中。
本发明也涉及牙膏组合物,该组合物包含:(a)氟化物和/或再矿化剂;(b)口腔可接受的溶媒;和(c)分散诱导剂组合物。本发明的分散诱导剂具有如上所述的化学式。上面也阐述了可包括于分散诱导剂组合物中的另外组分。通常,牙膏也包含月桂基硫酸钠或其它的硫酸盐。
其各种形式的氟化物是牙膏中的常用活性成分,用于防止空洞并促进牙釉质和骨的形成。任何氟化物源,例如氟化物盐可用于本发明的牙膏中。优选,氟化物是氟化钠(NaF)或单氟磷酸钠(Na2PO3F)。典型地,存在于牙膏中的氟化物的量的范围为每百万氟化物离子100-5000份,优选每百万1000-1100份。
在某些情况中,优选用再矿化剂取代或补充氟化物。在牙科用法的上下文中,再矿化一般指治疗牙齿以便预防龋齿,或减少其发生的机会,和另外增强牙齿以便它们可以恢复到其最初的健康状态。虽然可以认为氟化物是再矿化剂,但其它试剂常常代替氟化物或补充氟化物,以提供牙膏更强的清洁或再矿化性质。常用再矿化剂是钙盐,例如磷酸钙、硫酸钙、无水硫酸钙、硫酸钙半水合物、硫酸钙二水合物、苹果酸钙、酒石酸钙、丙二酸钙和琥珀酸钙。羟磷灰石纳米晶体和锌化合物也已显示是有效的再矿化剂。
口腔可接受的溶媒可以是可以用于使氟化物和/或再矿化剂和分散诱导剂释放至患者牙齿的本领域中已知的任何溶媒。口腔可接受的溶媒也可以是甘油、丙二醇、聚乙二醇、甘油三酸酯、甘油二酸酯、矿物油、有机油、精油、植物脂肪油及其组合。通常这些溶媒与水或水基溶剂组合使用。
牙膏组合物可包含在本领域中熟知的牙膏的其它组分。例如,牙膏组合物可包含碳酸氢钠、酶、维生素、草药、钙化合物例如磷酸硅酸钙钠、着色剂和/或矫味剂。也可添加脱敏剂。如在本领域中已知的,脱敏剂可以通过治疗由脱矿质引起的过敏而降低牙齿的敏感性,或通过使神经脱敏而抑制过敏症状。该组合物也可包含抗菌剂或抗斑剂。优选抗菌剂包括在预防龈炎、牙周炎和其它口腔疾病的组合物中。合适的抗菌剂包括三氯生、氯化锌、氯己定、苄索氯铵(benzthonium chloride)和氯化十六烷基吡啶鎓。
本发明也涉及用于治疗和/或预防牙斑、齿龈疾病、牙周病和/或口腔感染的口腔组合物。该口腔组合物包含口腔可接受的溶媒和分散诱导剂组合物。本发明的分散诱导剂具有如上所述的化学式。上面也阐述了可包括于分散诱导剂组合物中的另外组分。
口腔组合物可以是本领域技术人员已知的口腔卫生领域中的各种组合物。例如,口腔组合物可以是漱口剂、呼吸喷雾剂(breathspray)、洁齿剂、牙粉、增白条状物或预防性糊剂。如本领域中所熟知的,漱口剂通常用于帮助除去在口腔或咽喉中的粘液和食物颗粒。漱口剂通常包含防腐剂和/或抗斑组分,以杀灭引起龋齿、龈炎和口臭的菌斑。它们也可以包含抗空洞组分例如氟化物,以防止牙齿腐蚀。合适的漱口剂组分可于美国专利第5,968,480号中发现,该专利通过引用而整体结合到本文中。
同样,相同或相似的防腐剂、抗斑组分和抗空洞组分可以用于呼吸喷雾剂、洁齿剂包括凝胶洁齿剂、牙粉、增白条状物和预防性糊剂中。在美国专利第7,297,327号中公开了合适的呼吸喷雾剂组合物;在美国专利第5,989,526号中公开了合适的牙粉组合物,例如用于牙齿漂白组合物中的那些;在美国专利第6,514,483号中公开了合适的增白条状物;在美国专利第5,939,051号中公开了合适的洁齿剂和预防性糊剂组合物,包括牙齿磨擦剂,所有这些专利均通过引用而整体结合到本文中。
口腔可接受的溶媒成分与上述那些相似。然而,口腔可接受的溶媒将根据口腔组合物的期望一致性和期望的最终产品而改变。例如,漱口剂是液体形式,所以应该使用液体载体,通常为具有高百分比的水的载体。在另一方面,凝胶洁齿剂应该是凝胶形式,和将利用胶凝剂或使最终产品能够为凝胶形式的其它载体。口腔可接受的溶媒应该具有允许分散诱导剂组合物释放,同时也提供具有期望一致性的最终产品的性质。
口腔组合物也可以为口香糖、口气清新(breath)条状物、锭剂或薄荷糖(breath mint)的形式。口香糖通常是水不溶相或胶基质和甜味剂、矫味剂和/或食用色素的水溶相的组合。其它组分也可添加至口香糖,包括口气清新添加剂例如锌盐和磷酸盐、牙齿-增白添加剂例如二氧化硅和减少噬菌斑以缓解牙斑的添加剂。合适的口香糖组合物可于美国专利第6,416,744号和6,592,849号中发现,这两个专利均通过引用而整体结合到本文中。
口气清新条状物类似于口香糖,不同之处在于条状物设计在口中溶解,通常通过舌吸收。该条状物可以释放使口清新的生物活性成分以及功能性生物活性成分,例如维生素、矿物质、补充剂、药物和疫苗。
锭剂和薄荷糖通常为在矫味基质中含治疗剂的盘状固体。基质可以是硬冰糖、甘油胶或糖与足量粘质物的组合,以给予组合物要求的形式。分散诱导剂可代表治疗剂,或除本领域中已知的治疗剂外它可加入。在美国专利第7,025,950号中公开了合适的锭剂和薄荷糖组合物,该专利通过引用而整体结合到本文中。
口腔组合物也可以是置入口腔的牙用装置的清洁制剂形式。将牙用装置例如假牙、牙科橡皮障和某些类型的牙矫正架置入口腔一段时间,然后周期性地取出清洁。用于清洁牙用装置的清洁组合物应该以其清洁装置的惯用方式起作用,但也可包含治疗剂,当牙用装置与口腔接触时,该治疗剂可以有助于治疗或预防牙斑、齿龈疾病、牙周病和口腔感染。清洁组合物例如泡腾清洁剂用本领域中已知的含氯化合物的碱性混合物等制备。在美国专利第3,936,385号中公开了牙用装置的合适清洁组合物,该专利通过引用而整体结合到本文中。可以以使其能够在接触后涂覆牙用装置的方式,将分散诱导剂添加至清洁组合物。在将牙用装置引入口腔之后,分散诱导剂可以以治疗有效的方式与牙齿和口腔的其它元件相互作用,即以预防牙斑、齿龈疾病、牙周病和/或口腔感染。
本发明也涉及包含牙用物品和分散诱导剂的口腔使用物品。分散诱导剂具有以上所述化学式,并涂布、包封在或浸渍在牙用物品内。上面也阐述了可包括于分散诱导剂组合物中的另外组分。
在本领域中已知的各种牙用物品可用于本发明的该实施方案中。在一个实施方案中,牙用物品是牙线。在本领域中已知的任何纤维均可用于牙线中。合适的纤维包括聚酰胺(例如尼龙)、聚酯、聚丙烯、聚四氟乙烯、纤维素和棉花。尼龙和聚四氟乙烯纤维是用于牙线中的最常见纤维并代表优选的纤维。在美国专利第6,270,890号和6,289,904号中公开了合适的牙线,这两个专利均通过引用而整体结合到本文中。可使分散诱导剂组合物浸渍在纤维内,涂布在纤维上,或另外掺入牙线内。
牙线可用蜡或其它疏水性物质涂布或浸渍,以便易于在线处理期间使用。合适的蜡包括微晶蜡、蜂蜡、石蜡、巴西棕榈蜡和聚乙烯蜡。可将分散诱导剂组合物涂布在牙线上,作为蜡层的一部分,作为与蜡层连接的第二层或另一层,或如上所述施加至纤维。
牙用物品可以是用分散诱导剂组合物浸渍或涂布的牙签。牙签可由天然产物例如木材或人造组分包括各种塑料制备。在美国专利第7,264,005号中公开了合适的牙签,该专利通过引用而整体结合到本文中。
牙用物品也可以是牙用器具例如吸牙器、牙合堤、牙障、舌稳定器、压舌器或牙科医生或牙科助理医师可用于患者口中的牙用设备的任何其它部件。牙用器具的讨论可于美国专利第4,865,545号和5,152,686号中发现,这两个专利均通过引用结合到本文中。牙用器具与患者口腔接触的部分可用分散诱导剂组合物涂布。
牙用物品也可以是牙构造物,例如放置在牙齿上的镶盖、冠、嵌体、高嵌体或齿桥。牙构造物通常由金属合金、瓷、陶瓷、汞合金、丙烯酸酯聚合物或这些材料的组合制成。在美国专利第7,229,286号公开了合适的牙构造物,该专利通过引用而整体结合到本文中。分散诱导剂组合物可包埋在用于制备牙构造物的组合物中。或者,可在其制备之后将分散诱导剂组合物涂布在牙构造物上。
本发明也涉及含水组合物,该含水组合物施用至使用牙用物品的口腔,该含水组合物包含水和分散诱导剂组合物。各种牙用物品附接至或设计与水管线(water line)一起使用,以便水可以通过牙用物品分配,然后按规定路线从牙用物品至受试者的口腔。合适的牙用物品包括牙水管线、牙齿喷水器(dental water picks)等。
虽然自来水或纯化水可用于这些类型的牙用装置,但水源也可用添加剂补充,以便当与牙用物品一起使用时,水递送添加剂至受试者的口腔。在该情况下,补充至水中的添加剂是分散诱导剂组合物。
牙水管线和牙齿喷水器在本领域中已知,且经常被牙科医生和牙科助理医师使用。不同类型的牙水管线及其不同应用的讨论可于美国专利第5,785,523号中发现,该专利通过引用而整体结合到本文中。在美国专利第4,257,433号中公开了合适的喷水器,该专利通过引用而整体结合到本文中。
本发明也涉及将接触透镜清洁和/或消毒的方法。该方法包括用清洁和/或消毒溶液处理接触透镜,该清洁和/或消毒溶液含本发明的分散诱导剂。当贮藏在溶液中或当在体内使用时,接触透镜可以该方式处理。或者,分散诱导剂可以用于滴眼剂。
本发明还涉及治疗和/或预防受试者皮肤上的痤疮或其它生物膜相关的皮肤感染的方法。该方法包括在对治疗和/或预防痤疮或生物膜相关的皮肤感染有效的条件下,用本发明的分散诱导剂处理受试者的皮肤。分散诱导剂可存在于乳膏剂、软膏剂、搽剂、油膏剂、修面洗剂或须后润肤膏中。其也可存在于散剂、化妆品、乳膏剂、软膏剂、液体、肥皂、凝胶、化妆涂布器和/或固体、预定与皮肤接触或接近的织造或非织造材料。
本发明也涉及在受试者中治疗和/或预防慢性生物膜相关疾病的方法。该方法包括在对治疗和/或预防慢性生物膜相关疾病有效的条件下,将本发明的分散诱导剂给予受试者。治疗和/或预防的慢性生物膜相关疾病包括但不限于中耳感染、骨髓炎、***炎、结肠炎、***炎、尿道炎、动脉斑块、滑膜感染、沿组织筋膜的感染、呼吸道感染(例如与囊性纤维化患者的肺感染相关的感染、肺炎、胸膜炎、心包感染)、泌尿生殖道感染和胃或十二指肠溃疡感染。对于幽门螺旋杆菌(Helicobacter pylori)引起的胃或十二指肠溃疡,分散诱导剂将需要在低于5.5的pH下起作用。分散诱导剂可与抗微生物剂例如生物杀灭剂、表面活性剂、抗生素、防腐剂、去污剂、螯合剂或毒力因子抑制剂联合给予。在胃治疗的情况下,也可使用降低酸的疗法,例如抗酸剂、质子泵抑制剂、抗组胺药等。
本申请的另一个方面涉及一种溶液,该溶液包含分散诱导剂,该分散诱导剂包含:其中是碳-碳单键或双键,m是1或2,n是4-7,且R是羧酸,其中所述诱导剂以小于0.5%重量的浓度存在,且其中所述溶液的pH大于5。
本发明的又一个方面涉及一种组合物,该组合物包含选自以下组分中一种或多种的组分:生物杀灭剂、表面活性剂、抗生素、防腐剂、去污剂、螯合剂、毒力因子抑制剂、凝胶、聚合物、糊、可食用产物和可咀嚼产物。此外,该组合物包括分散诱导剂,该分散诱导剂包含:其中是碳-碳单键或双键,m是1或2,n是4-7,且R是羧酸。将诱导剂配制成非盐形式。
本发明也涉及一种溶液,该溶液包括2-癸烯酸的顺式异构体,其中该溶液选自皮肤软膏剂、牙膏和漱口剂,且其中该溶液基本上不含2-癸烯酸的反式异构体。如本文所解释的,假如反式异构体浓度的降低(顺式异构体没有变化)不增加生物活性,则该溶液基本上不含反式异构体。更优选顺式与反式的摩尔比至少为2。
本申请的另一种形式涉及一种溶液,该溶液包含2-癸烯酸的顺式异构体,其中该溶液选自皮肤软膏剂、牙膏和漱口剂,且其中所述溶液不含反式异构体。
本申请的另一种形式是一种方法,该方法包括提供接触透镜和包含浓度小于0.5%重量的分散诱导剂的溶液,所述诱导剂包含:其中是碳-碳单键或双键,m是1或2,n是4-7,且R是羧酸、盐、酯或酰胺,其中酯或酰胺是羧酸的电子等排体或生物等排体。然后用所述溶液处理接触透镜。
本发明的又一种形式是一种方法,该方法包括提供有皮肤病的受试者和pH大于5的溶液,其中该溶液包含浓度小于0.5%重量的分散诱导剂,所述诱导剂包含:其中是碳-碳单键或双键,m是1或2,n是4-7,且R是羧酸、盐、酯或酰胺,其中酯或酰胺是羧酸的电子等排体或生物等排体。然后用该溶液治疗皮肤病。
本发明也涉及包含一种或多种分散诱导剂和一种或多种添加剂组分的组合物。这些添加剂组分选自生物杀灭剂、表面活性剂、抗生素、防腐剂、去污剂、螯合剂、毒力因子抑制剂、凝胶、聚合物、糊、可食用产物和可咀嚼产物。将所述组合物配制成使其当与微生物产生的生物膜接触时,其中该生物膜在表面上包含基质和微生物,所述分散诱导剂选择性地作用于微生物并具有合适的生物反应,而不需要直接作用来将基质破坏。
本发明的另一个方面涉及治疗或预防受试者中由生物膜介导的病症的方法,该方法包括提供受试者,该受试者具有或易感生物膜介导的病症,该生物膜由微生物产生,因此该生物膜在表面上包含基质和微生物。在有效的使分散诱导剂不需要对基质直接作用,而选择性地作用于所述微生物并具有合适的生物反应的条件下,将分散诱导剂给予受试者,因此治疗或预防了受试者中由生物膜介导的病症。
本申请的又一个实施方案涉及处理或抑制表面上生物膜形成的方法。这包括提供具有或易感生物膜形成的表面,该生物膜由微生物产生,因此该生物膜在表面上包含基质和微生物。在有效的使分散诱导剂不需要对基质直接作用,而选择性地作用于所述微生物并具有合适的生物反应的条件下,将分散诱导剂给予表面,因此处理或抑制了表面上生物膜的形成。
实施例
提供以下实施例,以举例说明本发明的实施方案,但决无意限制其范围。实施例1-菌株和培养基
用于该研究的微生物包括得自B.H.Holloway的铜绿假单胞菌(Pseudomonas aeruginosa)PAOl、大肠杆菌(Escherichia coli)(ATCC 10798)、奇异变形杆菌(Proteus mirabilis)(ATCC 25933)、肺炎克雷伯氏菌(Klebsiella pneumoniae)(ATCC 10273)、金黄色葡萄球菌(Staphylococcus aureus)(ATCC 12602)、化脓性链球菌(Streptococcuspyogenes)(ATCC 19615)、枯草芽孢杆菌(Bacillus subtilis)(ATCC 6633)和白色念珠菌(Candida albicans)(ATCC 20260)和经空气传播污染在R2A板上收集的混合的未定义培养物。除非另外指定,否则所有的实验在改良的EPRI培养基中进行,该EPRI培养基包含0.005%硝酸铵、0.00019%KH2PO4、0.00063%K2HPO4(pH 7.0)和0.001%Hutner盐(Cohen-Bazire等,J.Cell.Comp.Physiol.49:35(1957),该文献通过引用而整体结合到本文中),其补充0.2%葡萄糖。白色念珠菌(C.albicans)生长在补充0.2%葡萄糖和0.1%蛋白胨的改良的EPRI培养基中。肺炎克雷伯氏菌(K.pneumoniae)、奇异变形杆菌(P.mirabilis)、金黄色葡萄球菌(S.aureus)和枯草芽孢杆菌(B.subtilis)生长在补充0.1%蛋白胨的改良的EPRI培养基中。化脓性链球菌(S.pyogenes)生长在10%脑心浸液肉汤中。实施例2-铜绿假单胞菌(P.aeruginosa)用过培养基的制备
为了制备无细胞的用过培养基,将于30℃下在改良的EPRI培养基中生长的铜绿假单胞菌(P.aeruginosa)PAO1的6mL过夜培养物,接种至4升的改良EPRI培养基中,并在连续搅拌下,室温温育10天。通过在4℃下,在13,000×g下离心15分钟(Sorvall RC 5B PlusCentrifuge,GSA Rotor;Thermo Electron Co.,Ashville,NC),使细菌细胞沉淀。将上清液取出,并通过0.45μm微孔型HA过滤器(Millipore.Co.,Billerica,MA),接着通过0.2μm,Acrodisc 32mm注射器过滤器(PALLCo.,East Hills,NY)在真空下过滤。用过培养基贮藏在4℃下。实施例3-CSM的制备
通过将80mL氯仿添加至分液漏斗中的250mL过滤的用过培养基中,来提取用过培养基的有机组分。在1hr的分离时间之后,将氯仿部分取出。使用Rotavapor R-3000旋转蒸发器(Büchi Laboratories,Flawil,Switzerland)在40℃下蒸发氯仿,并将剩余的有机物质再悬浮于6mL过滤的纳米纯水中,并使用Speed-Vac蒸发器***(SavantInstruments,Inc.,Hicksville,NY)蒸发至干,或冻干。然后将这些样品再悬浮于培养基或纯化水中。最终产物称为氯仿提取的用过培养基(CSM)。除非另外指明,CSM均以比在用过培养基中发现的高125倍的最终氯仿提取的有机碳浓度,用于实验中。实施例4-CSM的HPLC分级分离
使用C18Microsorb-mv反相柱(Varian Inc.),尺寸为250×4.6mm,通过高效液相色谱(HPLC)(Varian Prostar model 320,Varian Inc.,Palo Alto,CA),将CSM分离。柱装载100μL的CSM,并用乙腈/水梯度(2-75%),以1mL×min-1的流速洗脱29分钟。从2分钟开始,每分钟收集样品。合并HPLC流份,并在Speed Vac浓缩器(SavantInstruments,Inc.,Hicksville,NY)中浓缩,然后再悬浮于0.5mL改良的EPRI培养基或纯化水中。发现用70%乙腈/30%水,将活性HPLC流份从柱中洗脱出来。通过微量滴定板分散生物测定法,测定每次HPLC分离的活性流份。实施例5-微量滴定板分散生物测定
微量滴定板分散生物测定用于测试各种制剂的外源性诱导生物膜分散的能力。使用半分批培养法,使生物膜生长在微量滴定板孔的内表面上,其中将各孔内的培养基周期性地更换,以减少天然分散诱导因素的积聚。将以该方式生长的生物膜用分散诱导剂或无菌培养基处理,以将细胞释放至批量液体中,并通过测量光密度来评估分散的细胞数。简而言之,将无菌聚苯乙烯96孔板用丙酮蚀刻10秒,以形成用于微生物细胞附着的粗糙表面。在干燥24小时之后,板用150μL/孔的过夜培养物接种,该过夜培养物含有试验生物体,先用生长培养基稀释1∶20,然后在200rpm下,在30℃下振摇温育。将孔中的培养基每24小时更换,持续5天,并在第6天和第7天每12小时更换。然后在7小时后更换培养基。通过以下方法来测试分散诱导:添加150μL含分散诱导剂的生长培养基,在30℃下持续1hr,或添加无菌培养基作为对照。然后,通过移液管将含分散细胞的培养基转移至未蚀刻的微量滴定板中,并测定光密度(OD570)(ELx808吸收度微量板阅读器;BioTek Instruments,Inc.,Winooski,VT)。处理组由各种浓度的用过培养基、CSM、顺-2-癸烯酸、反-癸烯酸、癸酸和DSF组成。乙醇(10%)用作脂肪酸诱导剂样品的载体,并确定它对分散没有影响。使用该方法的结果在不同处理组的比较中很有意义,并确定分散活性是否具有统计学显著性。注意:微量滴定板分散生物测定不适合于确定诱导分散响应的绝对量,因为在半分批***中,对照和试验样品对自然分散敏感,测量对该自然分散的外源性诱导活性。所有的效力研究均使用生物膜管状反应器或流动池连续培养***来进行,且均基于总细胞计数和活细胞计数。实施例6-生物膜管状反应器中的分散生物测定
使铜绿假单胞菌(P.aeruginosa)PAO1生物膜培养物生长在如前面Sauer等所述的管状反应器中(K.Sauer等,J.Bacteriol.184:1140(2002),该文献通过引用而整体结合到本文中)。使用8根聚硅氧烷反应器管(81.5cm长×14mm ID),该反应器管经另外的聚硅氧烷管连接至8辊头蠕动泵和培养基贮器,来装配连续的单程管状反应器***。培养基通过管泵送至关闭的流出培养基贮器。在接种前,通过高压灭菌使装配的***灭菌。通过注射器注射,穿过从各反应器管开始上游1cm的隔膜,使聚硅氧烷管接种铜绿假单胞菌(P.aeruginosa)的2mL过夜培养物(含约1×108CFU mL-1)。允许细菌细胞附着(静止温育)至管,持续1小时,然后,以10.8mL hr-1的洗脱速率开始流动。在铜绿假单胞菌(P.aeruginosa)PAO1生物膜培养96小时之后,进行处理。该处理在连续和静止的条件下进行。
在连续处理下(图17A),流入的培养基从实验系(test line)中的新鲜培养基变成用过培养基,该用过培养基用2%葡萄糖改良,调节至中性并在添加前充气过夜。对照系(controlline)转换成新的系,该新的系含新鲜的改良EPRI培养基。从时间=0min开始,在1分钟的时间间隔,收集样品,并测定光密度。在时间=30min时添加用过培养基。将样品收集在冰上的试管中,接着用Tissue Tearor 985370型(Biospec Products,Inc.)在5000rpm下匀化30秒,以保证细胞的分离。通过用Ultrospec 3000分光光度计(Amersham Pharmacia Biotech,Inc.),在600nm下测定光密度,来测定细胞密度。
在静止处理的条件下,通过注射器注射,穿过从管状反应器开始上游2cm的接种口,将分散诱导剂加入,反应器体积用含诱导剂的培养基置换。直接添加用过培养基。在改良的EPRI中制备CSM或合成的分散诱导剂(例如顺-2-癸烯酸)并加入。在非流动条件下暴露1小时之后,将各聚硅氧烷管状反应器的81.5cm长度切掉,液体部分(包含释放的生物膜细胞)收集在冰上试管内,并通过用金属棒在实验室台上使管滚动以挤出保留在管腔内的细胞,来收集生物膜部分(K.Sauer等,J.Bacteriol.184:1140(2002),该文献通过引用而整体结合到本文中)。将样品收集在冰上,并如上所述进行匀化。细胞数通过以下方法来测定:通过在标准板计数琼脂培养基(Difco,Detroit,MI)上的平板涂布培养法;或通过在OD600的光密度,该方法通过校准至通过总细胞计数用显微镜测定的细胞数的标准曲线,来调节细胞数。分散效力使用光密度或生存力测量值来计算:实施例7-显微镜分析
装配连续培养单程流动池,以观察附着至玻璃基底膜的生物膜的生长和发育。流动池由铝构成,包含用玻璃盖玻片盖住的室1.0mm×1.4cm×4.0cm。使用Masterflex 8辊头蠕动泵,以0.13mL/分钟的流速,使无菌改良的EPRI培养基从10升的容器,通过聚硅氧烷管泵送到流动池。流过室的是雷诺数为0.17的层流,流体停留时间是4.3分钟。离开流动池的培养基经聚硅氧烷管排放至流出物贮器。整个***对外部环境关闭,但通过安装至各容器的0.2μm孔径可透气的过滤器来保持与大气压平衡。在流动条件下,穿过从流动池开始上游4厘米的隔膜,以3.0mL块剂量,接种对数期铜绿假单胞菌(P.aeruginosa)(约108CFU mL-1)。使用Olympus BX60显微镜和放大100倍的A100PL物镜或放大50倍的ULWDMSPlan长焦点距离的Olymus物镜,通过透射光或表面UV光照,观察附着于玻璃盖玻片内表面的细胞。使用Magnafire冷却型3芯片电荷耦合器件(CCD)照相机(Optronics Inc.,Galena,CA)捕获所有的图像,并存储为各数字化文件,用于以后检索和分析在流动池中生长最长达12天的铜绿假单胞菌(P.aeruginosa)。申请人以前的工作已经显示在连续培养7-9天之后铜绿假单胞菌(P.aeruginosa)发育为稳定状态的生物膜。稳定状态定义为因分离的生物膜细胞引起的流出物细胞计数(CFU)无变化;在稳定状态中,生物膜的生长与细胞通过分散或分离的损失达到平衡。在各实验过程中检查各细胞簇,并指定网格坐标,在试验过程中周期性地再检查。通过定位最接近随机选择的显微镜载物台坐标的簇,对随机的细胞簇进行尺寸测量。通过从簇的基底膜到顶点聚焦来测量各细胞簇,以确定其高度,使用载物台测微器在细胞簇的基部测量其宽度。细胞簇定义为包埋在附着于基底膜的表多糖基质中并缺乏运动性的细胞;通过观察在细胞簇内部的空间内自由游动的细菌,来测定细胞簇内的空隙面积。实施例8-生物膜发育的抑制
流动池用于在(上述的)玻璃基底膜的表面上培养细菌。使铜绿假单胞菌(P.aeruginosa)的生物膜在改良的EPRI培养基中,在CSM(稀释1∶125,以匹配在用过培养基中发现的氯仿提取的有机物质的浓度)的存在和不存在下,在99个小时的时间内,在室温下生长。在实验过程中,通过在各时间点使用50倍ULWD MSPlan物镜计数20个显微镜视野,来测定细菌在表面上的总细胞覆盖率和生物膜的平均厚度。使用图像分析软件ImagePro Plus,在72小时和99小时测定细胞总面积/cm2。通过测量生长72小时和99小时的20个随机细胞簇的平均最大高度,来测定厚度。使对照样品在没有添加CSM的改良EPRI培养基的存在下生长并测试。这些实验的结果显示,与在单独的ERPI培养基中生长的生物膜相比,当生物膜在CSM的存在下生长时,生长生物膜的表面区域覆盖率显著减少。与没有用CSM处理的样品相比,CSM的添加也引起在生长99小时之后生物膜细胞簇的平均厚度显著降低(图18)。实施例9-铜绿假单胞菌(P.aeruginosa)CSM和顺-2-癸烯酸的光谱分析
将在纯化水中制备的所有CSM样品均冻干,并再悬浮于用于各光谱分析的合适载体中。在所有试验中的CSM对照均由CSMHPLC产物和不含CSM的载体溶液组成,如微量滴定板分散生物测定所测定的,该CSM HPLC产物不诱导分散。实施例10-质谱分析
使样品再悬浮于载体溶液(50%水、50%甲醇和0.01%甲酸)中。使用高效、混合四极飞行时间质谱仪-XL混合LC/MS/MS***(Applied Biosystems,Foster City,CA,USA)-以阳离子模式,在室温下,配有API 150EXTM、API 3000TM和***(AppliedBiosystems)的IonSpray源,来进行质谱分析。使用Analyst QS 1.1版分析数据。实施例11-核磁共振(NMR)
使CSM和顺-2-癸烯酸样品再悬浮于1mL的氘代乙腈中,并***薄壁的NMR样品管(VWR)内。用300MHz质子NMR-Bruker AC300(Bruker Daltonics Inc.,Vilarica,MA,USA)进行分析。使图谱累积24小时。实施例12-气相色谱-质谱(GC-MS)
将CSM和浓度为0.01mg×mL-1-10mg×mL-1的顺-2-癸烯酸样品再悬浮于2mL的乙腈中。进行3步连续己烷萃取以除去可溶性有机样品物质。将己烷在水浴(55-70℃)中蒸发至干。接着将Puridine(250μL)添加至可溶性样品,以便注射至GC中。用Shimadzu QP5050AGC-MS***,使用氦作为载体和Restek(Columbia,MD)XTI-5GC柱(30m,0.25mm内径,0.25μm膜厚),1mL×min-1流速,获得图谱。所有分析均结合不分流注射和电子碰撞电离。GC和MS之间的界面温度维持在310℃。使用程序Lab Solutions,GCMS解决方案1.2版来分析数据。实施例13-红外光谱(IR)
在冻干前和后称重CSM样品和顺-2-癸烯酸样品,以确定添加到各样品中的KBr的量。KBr以样品质量的10倍添加,并使用研钵和研杵混合。使用Carver 4350人工压丸机(Carver Inc.,Wabash,IN,USA)将得到的粉末形成小丸。施加10吨的压力,持续10min。按1cm-1的分辨率,在3500cm-1-400cm-1范围内,在室温下,使用Bruker Equinox55FT-IR分光计,获得IR图谱。最终的图谱表示128次扫描的平均值。各样品均一式三份测量。实施例14-生物膜细菌对抗生素抗药
图1A图示说明生物膜细菌如何对添加的抗生素抗药,与生物杀灭剂和其它抗微生物处理显示的抗性相似。图1B阐述了如果除抗生素以外还添加分散诱导剂,那么被分散的细菌就会失去它们的抗性且变得对抗生素敏感。实施例15-诱导分散的化合物的影响
图2显示实际生物膜样品,该样品用本发明的诱导分散的化合物处理,得自铜绿假单胞菌(Pseudomonas aeruginosa)的培养物。在该实验中,在用添加的CSM试验前,使用单程流动池培养铜绿假单胞菌(P.aeruginosa)6天。
流动池由阳极化处理的铝构成,包含用玻璃盖玻片盖住的室1.0mm×1.4cm×4.0cm。使用Masterflex 8辊头蠕动泵,以0.13mlmin-1的流速,使无菌EPRI培养基从2升的容器通过聚硅氧烷管泵送到流动池。流过室的是雷诺数为0.17的层流,流体停留时间是4.3min。离开流动池的培养基经聚硅氧烷管排放至流出物贮器。整个***对外部环境关闭,但通过固定至各容器的0.2μm孔径可透气的过滤器来保持与大气压平衡。在流动条件下,穿过从流动池开始上游的4厘米隔膜,以3.0mL块剂量,接种对数期铜绿假单胞菌(P.aeruginosa)(约108CFU/ml)。使用Olympus BX60显微镜和放大50倍的ULWD MSPlan长焦点距离Olympus物镜,通过透射光观察附着至玻璃盖玻片内表面的细胞。使用Magnafire冷却型3芯片电荷耦合器件(CCD)照相机(OptronicsInc.,Galena,Calif.)捕获所有的图像,并存储为各数字化文件,用于以后检索和分析。在成熟的生物膜在流动池内发育之后,停止培养基流动,并将3mL的过滤CSM/无菌EPRI培养基添加至流动池。在用CSM处理前和期间取得在流动池内单个位置的透射光图像。图2显示在添加CSM前1min,在添加CSM之后5min,和在添加CSM之后30min,从该实验取得的图像。对照样品也以与试验样品同样的方式操作,不同之处在于6mL添加的EPRI培养基中不包括CSM。对照样品的结果显示生物膜细胞数量或生物膜结构没有变化,并且没有明显的分散。实施例16-生物膜细菌经过表型转换
在正常的生物膜发育过程中,生物膜细菌在成熟II期末经历表型的转变(图3),其中它们在生理上从主要生物膜的形式变成主要浮游生物的形式。在分散相期间生物膜的显微镜观察证明,细胞簇内的细菌变得能动(成熟期铜绿假单胞菌(P.aeruginosa)是不动的),而簇边缘周围的细菌保持固定。细菌可以在其中游动/颤动的细胞簇区域从(通常)中央位置容积生长,且最后在簇壁中造成裂口。细菌能够游过该裂口并进入大量液相,在细胞簇内留下空隙。
对分散响应的继续研究显示,细胞簇通过生长和分散的偶发事件而转变;相同的细胞簇常常经受许多这样的循环。多个分散和再生长事件一般导致细胞簇以类似于生长轮的模式发育,该生长轮可以显示分散已经发生的次数。通常,细胞簇将在分散事件期间完全地从基底膜分离(Stoodley等,″细胞簇从成熟混合种类的生物膜的生长和分离″Appl.Environ.Microbiol.67:5608-5613(2001),该文献通过引用而整体结合到本文中)。该结果认为是由于在细胞簇的基部,附着结构的减弱所致,该细胞簇允许流体完全分离簇。实施例17-在培养基停滞之后的细胞分离
图4描述了相衬显微照片的时间序列,显示在培养基停滞72小时之后细胞的分离。按照在上面的实施例3中所述的方法,用铜绿假单胞菌(P.aeruginosa)PAO1接种到流动池,且培养3天。选择这些生物膜培养3天是基于以下观察:在连续的流动下,在温育了9天之后,观察到铜绿假单胞菌(P.aeruginosa)生物膜内的细胞簇经历了自发的分散事件。在连续的流动下生长72天之后,停止培养基流动且在96小时内每2小时记录细胞簇的图像。在培养基停滞72小时之后,观察到流动池内的细胞簇解聚,并且细胞作为悬浮细菌进入批量液体培养基中(图4)。这些实验表明,停止流动诱导生物膜的分散响应。在这些实验中,分散不是简单地发生在细胞簇内,而是遍及生物膜中的所有簇。如图4所示,观察到只有直接附着于基底膜的那些细胞才没有游入批量液体内。实施例18-氯仿提取方法的开发
试验了各种生长和提取方法,以开发提取具有分散诱导活性的用过培养基活性部分的可靠方法。选择氯仿作为选择的提取溶剂,是由于它与HPLC分级分离程序的相容性,因为它导致窄范围的可提取有机化合物(通过质谱法测定)和因为它能够恢复生物活性量的分散诱导剂。目前用于氯仿提取用过培养基的方法如下:铜绿假单胞菌(P.aeruginosa)PAO1的细菌培养物在4升的EPRI培养基(包含:乳酸钠0.05g/l、琥珀酸钠0.05g/l、硝酸铵50.381g/l、KH2PO4 0.19g/l、K2HPO4 0.63g/l、Hutner金属盐溶液1ml和葡萄糖2.0g/l)中,在分批培养容器中,在室温下连续搅拌下生长6天。在生长后,通过在10,000×g下离心20分钟,从培养基中除去细菌,然后通过0.22μm孔径的过滤器将用过培养基过滤。分批使250ml的过滤的用过培养基与80ml的氯仿在分液漏斗中混合。在分离10分钟之后除去氯仿部分。然后用旋转蒸发器R-3000(Biichi Laboratories,Flawil,Switzerland)使氯仿样品在70℃下蒸发至干,并再悬浮于6mL的过滤的纳米纯水或EPRI培养基中。得自氯仿提取操作的最终产物在此处称为浓缩的用过培养基或CSM。图15显示比较CSM与用过培养基对生长在生物膜管状反应器中的连续培养生物膜的影响的结果。如先前所述,由在22℃下,在补充2.0克/升葡萄糖的EPRI培养基中生长9天的铜绿假单胞菌(P.aeruginosa)PAO1的培养物来制备CSM和用过培养基。在由32cm二氧化硅Masterflex 14号管组成的生物膜管状反应器中,在22℃下,将铜绿假单胞菌(P.aeruginosa)PAO1的生物膜培养6天。在第6天末,将6mL的各自补充2.0克/升葡萄糖的CSM、用过培养基或无菌的EPRI培养基添加至管中。在20分钟时间内,将各处理的管流出物收集并合并。测定合并的样品在570nm的光密度,以测定从各处理分散的相对细胞数。各实验重复进行5次。这些实验的结果证明,与用过培养基相比,氯仿提取的用过培养基、CSM在分散铜绿假单胞菌(P.aeruginosa)的生物膜中显示了更大的活性。
申请人观察到,在培养基流动已经停止几个小时之后,铜绿假单胞菌(P.aeruginosa)PAO1将从连续培养生物膜中分散,该生物膜生长在流动池反应器内玻璃基底膜上。该观察导致以下假设:生物膜的分散可因用作生物膜解聚诱导剂的细胞外信使的积聚引起。以下的观察支持该假设:铜绿假单胞菌(P.aeruginosa)的生物膜在分批培养瓶中将不形成,但将在恒化器的壁上形成,这表明分散信号的积累可防止生物膜的发育。此外,当铜绿假单胞菌(P.aeruginosa)的微集落按连续培养生长时,当它们达到40微米的最小直径和10微米的厚度时,将在它们的中央形成空洞(图6)。然而,在其中形成这些空隙的微集落尺寸取决于液体的流速。当生物膜反应器中的流动增快时,出现微集落空隙形成的直径和厚度也增大,这表明了分散诱导与传输之间的关系。这些观察结果暗示,由铜绿假单胞菌(P.aeruginosa)产生的细胞外物质对诱导生物膜分散起作用。
如果铜绿假单胞菌(P.aeruginosa)产生胞外诱导分散的化合物,则申请人推测将无细胞的用过培养基添加至成熟的铜绿假单胞菌(P.aeruginosa)生物膜应该引起细胞释放到大量的液体培养基中。当在反应器流出物中回收的细胞数量增加时,应该可检测到这些细菌。图7A描述了代表性的实验结果,其中生物膜在连续的流动下,用无细胞用过培养基处理70分钟,铜绿假单胞菌(P.aeruginosa)已经在该无细胞用过培养基中悬浮生长24小时;添加新鲜培养基以控制生物膜。在添加前,将用过培养基充气,补充葡萄糖并调节其pH至中性,以保证饥饿、氧气耗尽或pH的变化不对细菌的释放起作用。在添加用过培养基的20分钟内,与对照系相比,在流出的细胞数量中可检测到大的尖峰,表明生物膜细菌释放至用用过培养基处理的培养物的流出物内。在对照样品中也可检测到释放细胞的小的尖峰,可能表示对物理或机械作用的反应,该物理或机械作用与系转换至新鲜培养基贮器有关。
为了纯化用过培养基的活性分散诱导部分,使用氯仿提取铜绿假单胞菌(P.aeruginosa)的无细胞稳定期分批培养物,然后旋转蒸发氯仿,并使有机部分再悬浮于新鲜培养基或缓冲溶液中(导致氯仿可溶性有机部分增加125倍)。该制剂被称为CSM。为了测试CSM的分散诱导活性,使铜绿假单胞菌(P.aeruginosa)生物膜在聚硅氧烷管内按连续培养生长,并使生物膜暴露至用CSM改良的培养基中,持续1小时。在用新鲜培养基处理的对照系中,管状反应器的挤出的内容物显示大量完整的生物膜(图7B),而用CSM处理的管的内容物显示生物膜已经完全解聚(图7C)。在聚硅氧烷管内按连续培养生长的4天老生物膜的研究显示,通过释放至流出物的集落形成单位测定,用含CSM的培养基处理1小时有效释放平均87.4%(±1.4%)的生物膜细胞。显示用过培养基的平均分散效力为32.4%(±5.5%)。
显微镜检查法用于评估CSM对生物膜微集落的影响,该生物膜微集落在安装至显微镜的流动池的玻璃基底膜上按连续培养生长6天(K.Sauer等,J.Bacteriol.184:1140(2002),该文献通过引用而整体结合到本文中)。在添加CSM前,观察到发育良好的微集落包含固定并显示无活动迹象的细胞(图7D)。在与含CSM的培养基接触7分钟之后,微集落内的细胞开始颤动并显示积极的活动(图7E)。在30分钟后,微集落已经变得完全解聚,观察到细胞穿过培养基自由地游动(图7F)。当与自然分散比较时,观察到外源性诱导的分散从微集落的外部朝内部发展,而不是形成中央空隙,导致微集落的完全解聚。
当向流动池连续添加时,CSM调节用过培养基的浓度,显示在99小时的时间内显著抑制生物膜的发育,证明生物膜的平均厚度和表面积覆盖率均降低(图8)。在从第1天(生物膜微集落形成开始)到第6天的所有时间点,均可测量CSM对预先形成的生物膜的外源性分散诱导,在这期间之后开始发生自然分散。当冷冻下储藏时,CSM的活性显示持续长达6个月,而无明显的降低。通过乙酸乙酯提取用过培养基(以回收酰基-高丝氨酸内酯)不会产生具有分散活性的制剂。
由于已经证明了对铜绿假单胞菌(P.aeruginosa)形成的成熟和发育的生物膜的分散诱导,因此在下面测试在大肠杆菌(E.coli)的生物膜培养物、与铜绿假单胞菌(P.aeruginosa)混合的大肠杆菌(E.coli)生物膜培养物、源自空气传播污染物的未定义的混合细菌生物膜和对肺炎克雷伯氏菌(Klebsiella pneumoniae)、奇异变形杆菌(Proteusmirabilis)、化脓性链球菌(Streptococcus pyogenes)、枯草芽孢杆菌(Bacillus subtilis)、金黄色葡萄球菌(Staphylococcus aureus)和白色念珠菌(Candida albicans)形成的生物膜中,CSM诱导分散的能力。与对照相比,CSM在所有测试的样品中均显示出刺激显著的分散。这些实验的结果如图9中所示。在不同属的细菌和在酵母中,铜绿假单胞菌(P.aeruginosa)分散诱导剂激活分散的能力显示,它具有跨门和跨界的活性。
由于已经确定了CSM作为生物膜分散诱导剂的作用,因此鉴定了存在于CSM中的一种或多种活性分子。这由测定CSM的多个部分的分散活性开始,所述部分使用C-18反相高效液相色谱(HPLC),通过乙腈和水的等度梯度分离。洗脱的HPLC流份(按1分钟时间间隔收集)在Speedvac中干燥,以除去残留的乙腈,再悬浮于纯化水中,并通过微量滴定板分散生物测定法来测试,以确定分散活性。图10A显示CSM分级分离生物膜分散测定的结果。结果显示,由比例为70%/30%的乙腈/水,在22分钟洗脱的CSM的HPLC流份显示最高的活性。
活性HPLC CSM流份的质谱显示在171M/Z(mw=170)的具有低离子化活性的一致分子峰。该峰存在于所有显示分散活性的样品中,而在所有缺少分散活性的样品中没有。该峰也显示在用于制备CSM(包括新鲜培养基)的所有载液和溶剂中没有。170mw峰的质谱-产物离子分析、溶解度分析、H1-和C13核磁共振(NMR)光谱和红外(IR)光谱已经证明,170mw分子是双键位于2位碳的单不饱和C10-脂肪酸;2-癸烯酸。
为了证实22分钟CSM HPLC流份的170-mw分子(M/Z=171)与2-癸烯酸相同,使原始分子在质谱中变成碎片,以产生产物离子峰。用四极ms/ms分析活性CSM流份和2-癸烯酸的产物离子,以评估这两个分子之间的裂解差异。图12A显示171M/Z CSM样品与2-癸烯酸具有同一性。当用GC-MS分析时,未分离的CSM显示单一主峰,保留时间为7.6分钟,其与图12B中2-癸烯酸的相同。红外光谱证实2-癸烯酸的顺式异构体是从CSM分离的有机化合物,见图12C。
在该鉴别之后,合成各种分子量的单不饱和脂肪酸分子,并测试这些分子的分散活性。显示破坏野油菜黄单胞菌(X.campestris)的细胞絮凝物的DSF显示没有促进铜绿假单胞菌(P.aeruginosa)的分散。具有最高活性的化合物是2-癸烯酸的两种异构体。通过微量滴定板分散生物测定显示反式异构体(反-2-癸烯酸)仅在毫摩尔浓度才有活性,通常没有低的足以有资格作为细胞-细胞信号分子。图10B显示增加浓度的顺-2-癸烯酸对生长在微量滴定板中的铜绿假单胞菌(P.aeruginosa)生物膜培养物的分散活性。这些结果证明,顺式异构体(顺-2-癸烯酸)在1.0纳摩尔-10毫摩尔的浓度范围内有活性,在1.0纳摩尔显示比未浓缩的用过培养基更大的分散活性(即高于天然存在的诱导剂)。显微镜检查显示顺-2-癸烯酸作为分散诱导剂的活性与CSM活性相似,如图13中所示,完全破坏生物膜微集落。也测试顺-2-癸烯酸对大肠杆菌(E.coli)、肺炎链球菌(S.pneumonia)、奇异变形杆菌(P.mirabilis)、化脓性链球菌(S.pyogenes)、枯草芽孢杆菌(B.subtilis)、金黄色葡萄球菌(S.aureus)和白色念珠菌(C.albicans)生物膜培养物的活性,得到与CSM获得的那些相似的结果(图11)。
该研究显示,在分批和生物膜培养中由铜绿假单胞菌(P.aeruginosa)产生小信使脂肪酸分子顺-2-癸烯酸。已经证明该分子在铜绿假单胞菌(P.aeruginosa)形成的生物膜内和在革兰氏阴性和革兰氏阳性菌的范围内以及在酵母内诱导分散响应。分散响应是在群体内逃脱饥饿状态的机制,允许固定细胞有机会迁移到更有利的环境,并使剩余的群体稀疏,允许细胞获得增加的营养物。当生物膜微集落很小时,在细胞外基质中积聚的诱导剂通过扩散和对流转运除去。该除去在分批***中是不可能的。当细胞簇达到其中诱导剂不能从内部充分洗出的尺寸时(扩散的速率被产生的速率超过),诱导剂能够达到激活分散响应,从生物膜释放细胞所需的浓度。细胞-细胞信号分子对生物膜分散起作用的发现允许外源性诱导生物膜细菌转变至悬浮状态。在抗生物膜相关的感染和控制微生物生物结垢中,该分散诱导剂的使用可能导致增强的处理选项。
虽然本文已经详细地描绘和描述了优选的实施方案,但是对相关领域的技术人员来讲,可以进行各种修改、添加、替换等,而不背离本发明的精神将是显而易见的,这些修改、添加、替换等因此认为是在本发明的范围内,本发明的范围在权利要求中限定。
Claims (81)
1.一种组合物,所述组合物包含:
一种顺-2-癸烯酸分散诱导剂和
一种或多种添加剂组分,所述添加剂组分选自生物杀灭剂、表面活性剂、抗生素、防腐剂、去污剂、螯合剂、毒力因子抑制剂、凝胶、聚合物、糊、可食用产物和可咀嚼产物,将所述组合物配制成使其当与由微生物产生的生物膜接触时,其中该生物膜在一种表面上包含基质和微生物,所述分散诱导剂不需要对基质直接作用,而选择性地作用于所述微生物并具有合适的生物反应,以将所述生物膜破坏。
2.权利要求1的组合物,其中所述分散诱导剂以1μM-30mM的浓度存在于所述组合物中。
3.权利要求1的组合物,所述组合物的pH为1.5-4.5。
4.权利要求1的组合物,所述组合物的pH为4.5-8.0。
5.权利要求1的组合物,所述组合物的pH为6.8-7.4。
6.权利要求1的组合物,所述组合物的pH为8.0-9.8。
7.权利要求1的组合物,其中所述组合物是洁齿剂或漱口剂。
8.权利要求1的组合物,其中将所述组合物配制成使所述分散诱导剂是非杀菌的。
9.权利要求1的组合物,其中所述分散诱导剂以小于0.5%重量的浓度存在于所述组合物中。
10.权利要求1的组合物,所述组合物基本上不含乙醇。
11.权利要求1的组合物,所述组合物基本上不含甲醛。
12.权利要求1的组合物,所述组合物包含外科用胶。
13.一种表面,所述表面用权利要求1-12任一项的组合物涂布。
14.权利要求13的表面,所述表面是牙线。
15.权利要求13的表面,所述表面是接触透镜。
16.权利要求13的表面,所述表面是骨植入物。
17.一种顺-2-癸烯酸分散诱导剂在制备用于治疗或预防患者中由生物膜介导的病症的方法中的组合物的用途,所述方法包括:
提供患者,该患者患有或易感由生物膜介导的病症,该生物膜由微生物产生,因此所述生物膜在一种表面上包含基质和微生物;和
在有效的使分散诱导剂不需要对基质直接作用,而选择性地作用于所述微生物并具有合适的生物反应的条件下,将组合物给予所述患者,因此治疗或预防患者中由生物膜介导的病症。
18.权利要求17的用途,所述方法还包括:
将抗微生物处理与分散诱导剂的所述给予联合给予患者,所述抗微生物处理选自以下处理中的一种或多种:生物杀灭剂、表面活性剂、抗生素、防腐剂、去污剂、螯合剂、毒力因子抑制剂、超声波处理、放射处理、热处理和机械处理。
19.权利要求17的用途,其中治疗烧伤的患者。
20.权利要求17的用途,其中治疗患有牙斑、龋齿、齿龈疾病和/或口腔感染的患者。
21.权利要求17的用途,其中所述给予用洁齿剂、漱口剂、牙线、胶、条状物或刷子进行。
22.权利要求17的用途,其中治疗在皮肤上有痤疮或其它生物膜相关的皮肤感染的患者。
23.权利要求17的用途,其中治疗患有慢性生物膜相关疾病的患者。
24.权利要求23的用途,其中所述慢性生物膜相关疾病选自中耳感染、骨髓炎、***炎、囊性纤维化、结肠炎、***炎、尿道炎和胃溃疡或十二指肠溃疡。
25.权利要求17的用途,其中所述分散诱导剂以0.01μM-30mM的浓度给予。
26.权利要求17的用途,其中所述分散诱导剂以pH为1.5-4.9的组合物给予。
27.权利要求17的用途,其中所述分散诱导剂以pH为4.5-8.0的组合物给予。
28.权利要求17的用途,其中所述组合物的pH为6.8-7.4。
29.权利要求17的用途,其中所述组合物的pH为8.0-9.8。
30.权利要求17的用途,所述分散诱导剂以配制成使所述分散诱导剂为非杀菌的组合物给予。
31.权利要求17的用途,其中所述分散诱导剂以小于0.5%重量的浓度给予。
32.一种非治疗目的、处理或抑制表面上生物膜形成的方法,所述方法包括:
提供具有或易感生物膜形成的表面,该生物膜由微生物产生,因此该生物膜在表面上包含基质和微生物;和
在有效的使分散诱导剂不需要对基质直接作用,而选择性地作用于所述微生物并具有合适的生物效应的条件下,将顺-2-癸烯酸分散诱导剂给予所述表面,因此处理或抑制表面上生物膜的形成。
33.权利要求32的方法,其中所述表面是接触透镜。
34.权利要求32的方法,其中所述表面是选自以下的留置医疗装置:导管、呼吸器和通风器。
35.权利要求32的方法,其中所述表面是选自以下的植入医疗装置:支架、人工瓣膜、关节、缝合线、U形钉、起搏器、骨植入物和钉。
36.权利要求32的方法,其中所述表面选自***装置、桶状物、厨房用具、工作台面、淋浴帘、薄浆涂料、盥洗室、工业食品和饮料生产设施、地板和食品加工设备。
37.权利要求32的方法,其中所述表面是热交换器表面或过滤器表面。
38.权利要求32的方法,其中所述表面是选自以下的海上构筑物:船、桥墩、石油平台、水摄取口、筛和观察口。
39.权利要求32的方法,其中所述表面与水处理和/或分配***相联系。
40.权利要求39的方法,其中所述水处理和/或分配***选自饮用水处理和/或分配***、池和矿泉水处理***、制备操作中的水处理和/或分配***和牙科水处理和/或分配***。
41.权利要求32的方法,其中所述表面与提取石油的石油钻探、贮藏、分离、精制、分配和/或多孔介质的***相联系。
42.权利要求41的方法,其中所述石油钻探、贮藏、分离和/或分配的***选自石油分离列车、石油容器、石油分配管道和石油钻探设备。
43.权利要求32的方法,所述方法还包括:
将至少一种抗微生物处理与分散诱导剂的所述给予联合给予所述表面,所述抗微生物处理选自生物杀灭剂、表面活性剂、抗生素、防腐剂、去污剂、螯合剂、毒力因子抑制剂、超声波处理、放射处理、热处理和机械处理。
44.权利要求43的方法,其中所述分散诱导剂和所述抗微生物处理同时给予。
45.权利要求43的方法,其中所述分散诱导剂和抗微生物处理分别给予。
46.权利要求43的方法,其中将所述分散诱导剂浸透于所述表面。
47.权利要求43的方法,其中所述分散诱导剂以涂布所述表面的共聚物或凝胶给予。
48.权利要求43的方法,其中所述分散诱导剂以0.01μM-30mM的浓度给予。
49.权利要求43的方法,其中所述分散诱导剂以pH为1.5-4.9的组合物给予。
50.权利要求49的方法,其中所述分散诱导剂以pH为4.5-8.0的组合物给予。
51.权利要求43的方法,其中所述分散诱导剂的pH为6.8-7.4。
52.权利要求43的方法,其中所述分散诱导剂的pH为8.0-9.8。
53.权利要求32的方法,其中所述分散诱导剂以组合物给予,该组合物配制成使所述分散诱导剂为非杀菌的。
54.权利要求32的方法,其中所述分散诱导剂以小于0.5%重量的浓度给予。
55.权利要求32的方法,其中所述表面是骨植入物。
56.一种溶液,所述溶液包含:
顺-2-癸烯酸分散诱导剂,其中所述诱导剂以小于0.5%重量的浓度存在,且其中所述溶液的pH大于5。
57.权利要求56的溶液,所述溶液不含乙醇。
58.权利要求56的溶液,所述溶液不含甲醛。
59.权利要求56的溶液,其中所述pH基本上呈中性。
60.权利要求56的溶液,所述溶液选自皮肤软膏剂、牙膏和漱口剂。
61.权利要求56的溶液,其中所述诱导剂以非盐形式配制。
62.权利要求56的溶液,所述溶液还包含选自以下的一种或多种的组分:生物杀灭剂、表面活性剂、抗生素、防腐剂、去污剂、螯合剂、毒力因子抑制剂、凝胶、聚合物、糊、可食用产物和可咀嚼产物。
63.一种组合物,所述组合物包含:
选自以下的一种或多种的组分:生物杀灭剂、表面活性剂、抗生素、防腐剂、去污剂、螯合剂、毒力因子抑制剂、凝胶、聚合物、糊、可食用产物和可咀嚼产物,和
顺-2-癸烯酸分散诱导剂,所述诱导剂以非盐形式配制。
64.权利要求63的组合物,所述组合物是基本上不含乙醇的溶液。
65.权利要求64的组合物,其中所述溶液也基本上不含甲醛。
66.权利要求64的组合物,其中所述溶液基本上为pH中性。
67.权利要求63的组合物,所述组合物为选自以下的制剂:皮肤软膏剂、牙膏和漱口剂。
68.一种方法,所述方法包括:
a)提供接触透镜和溶液,所述溶液包含浓度小于0.5%重量的顺-2-癸烯酸分散诱导剂;和
b)用所述溶液处理所述接触透镜。
69.权利要求68的方法,其中所述溶液基本上不含乙醇。
70.权利要求68的方法,其中所述溶液基本上不含甲醛。
71.权利要求68的方法,其中所述溶液的所述pH基本上呈中性。
72.权利要求68的方法,其中所述接触透镜贮藏在所述溶液中。
73.权利要求68的方法,其中所述诱导剂以非盐形式配制。
74.权利要求68的方法,其中所述溶液还包含选自以下的至少一种组分:生物杀灭剂、表面活性剂、抗生素、防腐剂、去污剂、螯合剂和毒力因子抑制剂。
75.一种顺-2-癸烯酸分散诱导剂在制备用于下述方法中的组合物的用途,所述方法包括:
a)提供患有皮肤病的患者和pH大于5的溶液,所述溶液包含浓度小于0.5%重量的分散诱导剂;和
b)用所述溶液治疗所述皮肤病。
76.权利要求75的用途,其中所述溶液基本上不含乙醇。
77.权利要求75的用途,其中所述溶液基本上不含甲醛。
78.权利要求75的用途,其中所述溶液的所述pH基本上呈中性。
79.权利要求75的用途,其中将所述溶液配制成软膏。
80.权利要求75的用途,其中所述诱导剂以非盐形式配制。
81.权利要求75的用途,其中所述溶液还包含选自以下的至少一种组分:生物杀灭剂、表面活性剂、抗生素、防腐剂、去污剂、螯合剂和毒力因子抑制剂。
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BRPI0811530A2 (pt) | 2014-11-18 |
DK200970201A (en) | 2009-11-11 |
CA2684150C (en) | 2016-10-04 |
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