CN109689861A - 用于治疗痤疮的组合物和方法 - Google Patents
用于治疗痤疮的组合物和方法 Download PDFInfo
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- CN109689861A CN109689861A CN201780043587.6A CN201780043587A CN109689861A CN 109689861 A CN109689861 A CN 109689861A CN 201780043587 A CN201780043587 A CN 201780043587A CN 109689861 A CN109689861 A CN 109689861A
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Abstract
在某些方面,本公开涉及与靶向痤疮丙酸杆菌的突变噬菌体有关的组合物和方法。在某些方面,本文所述的组合物和方法可用于治疗痤疮。
Description
相关申请案
本申请要求2016年5月15日提交的美国临时专利申请序列号62/336,680的优先权权益,该临时专利申请据此通过引用整体并入。
关于联邦资助研究的声明
本发明是在美国国立卫生研究院授予的授权号AR060382和AR060655的政府支持下完成的。政府拥有本发明的某些权利。
发明领域
本发明涉及宿主范围扩大的痤疮丙酸杆菌(Propionibacterium acnes)噬菌体用于治疗痤疮的用途。
发明背景
痤疮是美国人群情绪和身体发病率的重要原因。寻常痤疮影响超过4500万人,并且美国超过80%的人报告称在他们的生活中遭受痤疮。美国消费者每年花费超过12亿美元进行痤疮治疗。该疾病可显著影响患者的自尊,并产生诸如疤痕等长期影响。
痤疮丙酸杆菌(P.acnes),参与痤疮发病机制的主要物种,越来越多地对抗生素疗法产生抗性。革兰氏阳性皮肤共生痤疮丙酸杆菌是人皮脂腺毛囊的主要栖居者(2),并且被认为在寻常痤疮的发病机制中起主要作用,部分是通过引发宿主炎症响应来起作用(3)。青春期时痤疮丙酸杆菌定殖显著增加,青春期是痤疮通常出现的时间,并且患有痤疮的青少年的皮肤上存在的痤疮丙酸杆菌比年龄相仿的健康对方多100倍(4)。抗生素在痤疮中的功效与减少皮肤上的痤疮丙酸杆菌细菌数量,以及直接的抗炎特性有关(5),这反映了痤疮的多因素病因。正如在多达60%的临床分离株中所测量的(6-8),痤疮丙酸杆菌的抗生素抗性菌株的出现,突出了对改进治疗剂的需求(5)。
因此,本领域长期需要提供可用于治疗严重痤疮的方法和组合物。本文描述的本发明提供了此类组合物和方法。
发明内容
本文提供了与治疗和/或预防皮肤病诸如痤疮有关的方法和组合物。在一些方面,本文提供了痤疮丙酸杆菌(P.Acnes)噬菌体突变体(例如,规律成簇的间隔短回文重复序列(CRISPR)逃逸突变体)和包含噬菌体突变体的组合物(例如,药物组合物),所述噬菌体突变体能够感染噬菌体抗性痤疮丙酸杆菌。本文提供了通过施用本文公开的噬菌体突变体和组合物治疗或预防受试者的痤疮的方法。在一些实施方案中,突变体在选自1、3和4的原间隔序列中包含一种或多种突变。在一些实施方案中,突变选自:T6502G、C6514A、G2762T、T2757C、G5919T、C5917A、A5892C、P9.1-2A、P9.1-2B、P9.1-3和P9.1-4。噬菌体可包含与SEQID NO:1或其反向互补序列具有至少约95%序列同源性的核苷酸序列;并且所述核苷酸序列包含选自对SEQ ID NO:1的A2、A3、T5、C6、T7、T8、C9、G11、G12、G13、G14、C17、G20、G21和G22的一个或多个核苷酸的突变。所述噬菌体突变体可包含选自A2T、A2C、A3C、T5G、G11T、G14T、C17A、G20T、G21C、C22G和C22T的对SEQ ID NO:1的一种或多种突变。在一些实施方案中,噬菌体的基因9包含所述核苷酸序列。在一些实施方案中,噬菌体包含与SEQ ID NO:2或其反向互补序列具有至少约95%序列同源性的核苷酸序列;所述核苷酸序列包含对选自SEQ ID NO:2的A2、A3、T5、C6、T7、T8、C9、G11、G12、G13、G14、C17、T20、C21和T22的一个或多个核苷酸的突变。所述核苷酸序列可包含选自A2T、A2C、A3C、T5G、G11T、G14T、C17A、T20G、C21G、T22G和T22C的对SEQ ID NO:2的一种或多种突变。在一些实施方案中,噬菌体的基因9包含所述核苷酸序列。
在一些实施方案中,噬菌体包含与SEQ ID NO:3或其反向互补序列具有至少约95%序列同源性的核苷酸序列;所述核苷酸序列包含选自SEQ ID NO:3的A2、A3、A5、T6、T7、G8、A9、T11、T12、G13、G14、T20、G23、T25、T30和G31的一个或多个核苷酸的突变。所述核苷酸序列可包含选自T7C、T20G、G23A、T25G、T30G和G31T的对SEQ ID NO:3的一种或多种突变。在一些实施方案中,噬菌体的基因16包含所述核苷酸序列。
在一些实施方案中,噬菌体突变体包含与SEQ ID NO:4或其反向互补序列具有至少约95%序列同源性的核苷酸序列;所述核苷酸序列包含选自SEQ ID NO:4的A2、A3、T5、G6、C7、G8、C9、A11、A12、C13、A14、A15、A16和G18的一个或多个核苷酸的突变。在一些此类实施方案中,所述核苷酸序列包含选自A3T、A3C、A3G、C7A、C9A、A12G、C13A、A15G、A16C、A16T和G18T的对SEQ ID NO:4的一种或多种突变。在一些实施方案中,噬菌体的基因3包含所述核苷酸序列。
在一些实施方案中,噬菌体包含与SEQ ID NO:5或其反向互补序列具有至少约95%序列同源性的核苷酸序列;所述核苷酸序列包含选自SEQ ID NO:5的A2、A3、T5、G6、C7、G8、C9、A11、A12、C13、A14、G15、T16和T18的一个或多个核苷酸的突变。在一些此类实施方案中,所述核苷酸序列包含选自A3T、A3C、A3G、C7A、C9A、A12G、C13A、G15A、T16C、T16A和T18G的对SEQ ID NO:5的一种或多种突变。在一些实施方案中,噬菌体的基因3包含所述核苷酸序列。
在一些实施方案中,噬菌体包含与SEQ ID NO:6或其反向互补序列具有至少约95%序列同源性的核苷酸序列;所述核苷酸序列包含选自SEQ ID NO:6的A2、A3、G5、C6、A7、G8、C9、A11、T12、C13、T14、A31、T33和G35的一个或多个核苷酸的突变。在一些此类实施方案中,所述核苷酸序列包含选自C6A、A7G、G8T、A31G、T33G和G35A的对SEQ ID NO:6的一种或多种突变。在一些实施方案中,噬菌体的基因7包含所述核苷酸序列。
在一些实施方案中,所述噬菌体的基因组与SEQ ID NO:7具有至少约95%、96%、97%、98%或99%的序列同源性,并且所述噬菌体包含选自G2761T、T2762C、G2767T、T2771C、T2771G、C6477A、A6507C、A6508C、T13160G、T13170G、G13171T、C13734A、T20501G、C23365A、G27713T、T28115G和G28199T的一种或多种突变。
在一些实施方案中,前述权利要求中任一项所述的噬菌体,其中所述噬菌体的基因组与SEQ ID NO:12具有至少约95%、96%、97%、98%或99%的序列同源性,并且所述噬菌体包含选自T2757C、G2760T、G2762T、T2766C、G3704T、C5890A、C5890T、A5892C、C5917A、G5919T、A6499C、T6502G、G6508T、G6511T、C6514A、A12404C、C16536A、G17863T和G26907A的一种或多种突变。
在一些方面,本文提供了包含本文公开的噬菌体的药物组合物。所述药物组合物可包含一种或多种抗微生物剂,诸如抗痤疮剂(例如,类视黄醇、过氧化苯甲酰和抗生素)。可以配制药物组合物用于局部使用。
本文提供了治疗受试者(例如,有需要的受试者)的痤疮的方法,该方法是通过施用治疗有效量的本文公开的组合物(例如,药物组合物,其包含一种或多种能够感染噬菌体抗性痤疮丙酸杆菌(P.Acnes)的痤疮丙酸杆菌(P.Acnes)噬菌体突变体。痤疮可能与噬菌体抗性痤疮丙酸杆菌相关。在一些实施方案中,所述噬菌体突变体是规律成簇的间隔短回文重复序列(CRISPR)逃逸突变体。在一些实施方案中,噬菌体突变体是本文公开的噬菌体突变体。
附图简述
专利或申请文件含有至少一张彩色附图。含彩色附图的本专利或专利申请公布的副本将根据要求和支付必要费用后由专利局提供。
出于说明本发明的目的,在附图中描绘了本公开的某些实施方案。然而,本公开不限于附图中描绘的实施方案的精确布置和手段。
图1描绘了痤疮丙酸杆菌噬菌体P100D的基因组图谱。
图2描绘了噬菌体逃逸突变体中的突变。在四种突变体的每一种中,突变(加下划线)位于三个原间隔序列中;1(黄色),3(绿色)和4(棕色)。
图3显示了ATCC_C(上)和ATCC_T(下)的连续稀释,显示了斑块形态类型。
图4描绘了分离的噬菌体逃逸突变体的数量并显示了斑块形态类型。
图5描绘了噬菌体逃逸突变体中的突变。
图6描绘了P9.1突变体中原间隔序列突变的序列。
图7是两种含有CRISPR的噬菌体抗性分离株的序列说明。
图8描绘了匹配B101.9间隔序列的痤疮丙酸杆菌噬菌体PS。
图9描绘了匹配B166.8间隔序列的痤疮丙酸杆菌噬菌体PS。
图10显示P91逃逸突变体有效感染对野生型噬菌体具有抗性的分离株。
图11显示P91逃逸突变体有效感染对野生型噬菌体具有抗性的分离株。B101.9上分离的突变体感染该分离株和B66.8,其中在B66.8上分离的突变体仅感染该分离株。
图12显示CRISPR逃逸突变体中的PS和PAM含有点突变。
图13显示由在B66.8上首先分离的突变体获得,然后通过B101.9传代的二次逃逸突变体有效感染B101.9并在B101.9PS-1PAM中含有点突变。
图14显示非抗性分离株上的逃逸突变体的宿主范围不受影响。
图15描绘了噬菌体逃逸突变体中的突变。
具体实施方式
I.综述
当前疗法不充分,基于噬菌体的疗法提供了一种新的抗微生物方法用于痤疮治疗。由于临床菌株之间的抗性,痤疮的口服抗生素疗法往往不成功(6-8),并且可导致全身不良效应:胃肠不适、光敏性、阴道酵母菌感染和牙齿变色。局部用类视黄醇导致刺激和光敏性,而全身用类视黄醇有效,但具有多系统副作用,包括肝毒性和致畸性。因此,非常需要开发特异性靶向痤疮丙酸杆菌的更安全且更有效的疗法。
噬菌体疗法。尽管噬菌体疗法已经使用了90多年(10),但在美国的使用受限于抗生素的发现和长期存在的关于功效的问题(11,12)。然而,致病细菌中抗生素抗性的出现刺激对噬菌体疗法重新燃起兴趣。重要的是,噬菌体已经给人类施用而没有毒性(13),并且已经在感染痢疾志贺菌(Shigella dysenteriae)(14)、大肠埃希氏菌(Escherichia coli)(15)和皮肤金黄色葡萄球菌(Staphylococcusaureus)(16-18)的动物模型中证实了噬菌体疗法的功效。局部噬菌体疗法已用于有效治疗假单胞菌属(Pseudomonas)感染,所述感染是豚鼠模型中皮肤移植的并发症(19),并且已经证实其在人类烧伤受害者和慢性耳部感染犬类中的治疗实用性(20,21)。FDA批准了由六种单独纯化的噬菌体组成的噬菌体混合物用于抵抗肉类和家禽产品中的单核细胞增多性李斯特菌(Listeriamonocytogenes)(10)并且已经批准了用于防治大肠埃希氏菌(E.coli)污染的类似产品。目前,许多公司正积极开发治疗性噬菌体(10),并且有几种活性噬菌体治疗试验(ClinicalTrials.gov)。尽管如此,许多人类细菌感染对噬菌体治疗提出了严峻挑战,其剂量、特异性、施加途径、抗性、清除率和免疫力仍然不明确。相比之下,痤疮是一种严重但不危及生命的疾病,对局部敷用有响应,并为推进噬菌体治疗方法提供了一种具吸引力的模式。
已经开发出策略来克服噬菌体抗性的可能(22),包括:i)高密度的噬菌体颗粒以达到“淹没阈值”(23),ii)噬菌体“混合物”含有靶向不同细菌受体的噬菌体的混合物;和/或iii)协同作用的噬菌体和抗生素的组合(24)。使用高噬菌体剂量和噬菌体衍生的脓菌素提供被动疗法,导致细菌裂解。这些方法缺乏利于噬菌体疗法的完整噬菌体颗粒的宿主依赖性扩增。基于细胞内溶素的噬菌体衍生产品是针对一些细菌的高效抗微生物剂,并且不可检测到抗性(25-27)。
在痤疮中使用局部噬菌体疗法代表了一种创新方法,其避免全身疗法相关的复杂性。此外,这将提供一种直接且特异性靶向痤疮丙酸杆菌的方式。
II.定义
如本文所用,术语“约”是指指定值+或-10%的值范围。例如,除非明确地与上下文相矛盾,否则短语“约200”包括200的+或-10%,或180至220。
如本文中所用,术语“施用”意指将组合物实际物理引入到患者体内或表面(视情况而定),导致与痤疮丙酸杆菌相关的痤疮接触。根据本发明考虑了将组合物引入宿主或细胞内的任何和所有方法;该方法不依赖于任何特定的引入方式,也不应如此解释。引入方式是本领域技术人员公知的,并且也在本文中进行了举例说明。
如本文中所用,“组合”施用是指同时和依次施用两种或更多种药剂或组合物。如本文中所用,同时或组合施用意指两种或更多种药剂或组合物在共同治疗方案的过程中(a)同时或(b)在不同时间施用给受试者。在后一种情况下,所述两种或更多种药剂或组合物在足够接近的时间内施用以达到预期效果。
如本文中所用,术语“噬菌体”是指在细菌内感染和复制的病毒。噬菌体由包封DNA或RNA的基因组的蛋白质组成。噬菌体在其基因组注入细菌细胞质后在细菌内复制。噬菌体包括“裂解性噬菌体”,其破坏细菌代谢并导致细菌裂解,即裂开。在优选的实施方案中,本公开的噬菌体能够感染痤疮丙酸杆菌。在优选的实施方案中,本公开的噬菌体能够感染多种痤疮丙酸杆菌菌株。在优选的实施方案中,本公开的噬菌体包含克服噬菌体抗性的突变。
如本文中所用,术语“有效量”、“有效剂量”、“足够量”、“对……有效的量”、“治疗有效量”或其语法等效形式意指足以产生所需结果,改善或以某种方式减少症状或停止或逆转疾病进展,并提供临床医生或其它有资格的观察者所指出的症状的主观缓解或客观鉴别的改善的剂量。通过施用本文所述的药物组合物改善特定病症的症状是指可以与药物组合物的施用相关的任何减轻,无论是永久的还是暂时的,持久的还是短暂的。
术语“填料”意指药学上可接受的填充剂,其可利于生产和冻干过程中的材料处理。合适的填料包括无机盐,诸如氯化钠,和水溶性糖或糖醇,诸如蔗糖、麦芽糖、甘露糖醇或海藻糖。
术语“分离的”、“纯化的”或“生物纯的”是指材料大体上或基本上不含在其天然状态下发现的通常伴随其的组分。
术语“调节”是本领域公认的并且是指上调(即,激活、刺激、增加)或下调(即抑制、阻遏、减少或降低)一种响应,或呈组合或分开的两个响应。
如本文中所用,“任选的”或“任选地”意指随后描述的事件或情形可能发生或可能不发生,并且该描述包括所述事件或情形发生的情况和不发生的情况。
如本文中所用,术语“突变”是指核酸序列(与野生型或正常核酸序列相比)的变化,其改变或消除所编码的多肽的功能,其改变或消除产生的所编码的多肽的量,或其改变或消除已获得突变的核酸的调节功能。突变包括但不限于本领域已知的点突变、缺失、插入、倒位、重复等。
如本文中所用,术语“肠胃外”途径是指除口服和局部途径以外的途径。适用于本发明的肠胃外途径可以是例如鼻途径。
如本文中所用,术语“噬菌体抗性”是指细菌抵抗噬菌体感染的能力增加。在优选的实施方案中,噬菌体抗性与细菌编码的规律成簇的间隔短回文重复序列(CRISPR)相关。
如本文中所用,术语“药学上可接受的”是指组合物在生理上可耐受并且当施用于受试者(优选人类受试者)时通常不产生过敏或类似不良反应。优选地,如本文中所用,术语“药学上可接受的”意指经联邦或州政府监管机构批准或列入美国药典或其它公认药典中用于动物且更特别是用于人类中。
如本文中所用,术语“治疗”包括抑制病理状态、病症或疾病,例如阻止或减少病理状态、病症或疾病或其临床症状的发展;或缓解病理状态、病症或疾病,例如致使病理状态、病症或疾病或其临床症状消退。这些术语还涵盖治疗和治愈。治疗意指改善或以其它方式有益地改变病理状况、病症或疾病的症状的任何方式。优选地,需要此类治疗的受试者为哺乳动物,更优选为人。
“w/v”是指重量/体积。
III.组合物
发明人惊奇且出乎意料地观察到施用突变痤疮丙酸杆菌噬菌体对治疗痤疮有用。此外,本文所述的组合物可用于治疗噬菌体抗性痤疮丙酸杆菌。
痤疮丙酸杆菌菌株及分离和确定菌株类型的方法是本领域技术人员已知的(参见WO2013/142378,其通过引用并入本文)。
在某些实施方案中,本公开提供能够感染噬菌体抗性痤疮丙酸杆菌的突变痤疮丙酸杆菌噬菌体。在某些实施方案中,所述噬菌体突变体是规律成簇的间隔短回文重复序列(CRISPR)逃逸突变体。在某些实施方案中,噬菌体突变体在选自1、3和4的原间隔序列中包含一种或多种突变。在某些实施方案中,所述噬菌体突变体包含选自以下的一种或多种突变:T6502G、C6514A、G2762T、T2757C、G5919T、C5917A和A5892C。在某些实施方案中,所述噬菌体突变体选自P9.1和衍生物P9.1-2A、P9.1-2B、P9.1-3和P9.1-4。
噬菌体可包含与SEQ ID NO:1(GAAGTCTTCTGGGGTGCAGGGCATGTTGGCTGAGCG)或其反向互补序列具有至少约95%、96%、97%、98%或99%序列同源性的核苷酸序列。SEQ IDNO:1是噬菌体P9.1基因9的子序列(SEQ ID NO:12的残基6445-6735)。该子序列可以被痤疮丙酸杆菌菌株B101.9的原间隔序列1识别。所述核苷酸序列可包含对选自SEQ ID NO:1的G1、A2、A3、G4、T5、C6、T7、T8、C9、T10、G11、G12、G13、G14、C17、G20、G21和G22的一个或多个核苷酸的突变。在优选的实施方案中,核苷酸序列包含对选自SEQ ID NO:1的A2、A3、T5、G11、G14和C17的一个或多个核苷酸的突变。核苷酸序列可包含一种或多种选自G1A、A2T、A2C、A3C、G4A、T5G、T7G、T8C、T10G、G11T、G13T、G14T、C17A、G20T、G21C、C22G和C22T的突变。在优选的实施方案中,核苷酸序列包含一种或多种选自A2T、T5G、G11T、G14T和C17A的突变。在一些实施方案中,噬菌体包含至少一个在天然存在的噬菌体中不存在的突变,例如所述一种或多种突变可包括至少一个在噬菌体P1.1、P9.1、P14.4、P100.1、P100A、P100D、P101A、P104A、P015、ATCC_C或ATCC_T中并非天然存在的突变。
噬菌体可包含与SEQ ID NO:2(GAAGTCTTCTGGGGTGCAGTCTATGTTGGCTGAGCG)或其反向互补序列具有至少约95%、96%、97%、98%或99%序列同源性的核苷酸序列。SEQ IDNO:2是噬菌体P1.1基因9的子序列(SEQ ID NO:7的残基6453-6743)。该子序列可以被痤疮丙酸杆菌菌株B101.9的原间隔序列1识别。所述核苷酸序列可包含对选自SEQ ID NO:2的G1、A2、A3、G4、T5、C6、T7、T8、C9、T10、G11、G12、G13、G14、C17、T20、C21和T22的一个或多个核苷酸的突变。在优选的实施方案中,核苷酸序列包含对选自SEQ ID NO:2的A2、A3、T5、G11、G14和C17的一个或多个核苷酸的突变。核苷酸序列可包含一种或多种选自G1A、A2T、A2C、A3C、G4A、T5G、T7G、T8C、T10G、G11T、G13T、G14T、C17A、T20G、C21G、T22G和T22C的突变。在优选的实施方案中,核苷酸序列包含一种或多种选自A2C和A3C的突变。在一些实施方案中,噬菌体包含至少一个在天然存在的噬菌体中不存在的突变,例如所述一种或多种突变可包括至少一个在噬菌体P1.1、P9.1、P14.4、P100.1、P100A、P100D、P101A、P104A、P015、ATCC_C或ATCC_T中并非天然存在的突变。
噬菌体可包含与SEQ ID NO:3(TAAGATTGAGTTGGCTGAGTCGGATGTGTTGCGGTT)或其反向互补序列具有至少约95%、96%、97%、98%或99%序列同源性的核苷酸序列。SEQ IDNO:3是噬菌体P1.1基因16的子序列(SEQ ID NO:7的残基12239-13399)。该子序列可以被痤疮丙酸杆菌菌株B66.8的原间隔序列1识别。所述核苷酸序列可包含对选自SEQ ID NO:3的A2、A3、A5、T6、T7、G8、A9、T11、T12、G13、G14、T16、G19、T20、G23、T25、T30和G31的一个或多个核苷酸的突变。在优选的实施方案中,核苷酸序列包含对选自SEQ ID NO:3的T20、T30和G31的一个或多个核苷酸的突变。核苷酸序列可包含一种或多种选自T7C、T16A、T16G、G19A、T20G、G23A、T25G、T30G和G31T的突变。在优选的实施方案中,核苷酸序列包含一种或多种选自T20G、T30G和G31T的突变。在一些实施方案中,噬菌体包含至少一个在天然存在的噬菌体中不存在的突变,例如所述一种或多种突变可包括至少一个在噬菌体P1.1、P9.1、P14.4、P100.1、P100A、P100D、P101A、P104A、P015、ATCC_C或ATCC_T中并非天然存在的突变。
噬菌体可包含与SEQ ID NO:4(CAACTGCGCCAACAAACGCATCTGATCCGAATACGG)或其反向互补序列具有至少约95%、96%、97%、98%或99%序列同源性的核苷酸序列。SEQ IDNO:4是噬菌体P9.1基因3的子序列(SEQ ID NO:12的残基1881-3206)(SEQ ID NO:15的残基6445-6735)。该子序列可以被痤疮丙酸杆菌菌株B101.9和B66.8的原间隔序列3识别。所述核苷酸序列可包含对选自SEQ ID NO:4的A2、A3、C4、T5、G6、C7、G8、C9、C10、A11、A12、C13、A14、A15、A16和G18的一个或多个核苷酸的突变。在优选的实施方案中,核苷酸序列包含对选自SEQ ID NO:4的A3、C7、C9和A12的一个或多个核苷酸的突变。核苷酸序列可包含对选自A3T、A3C、A3G、C4T、C7A、C7G、C9A、C10T、A12G、C13A、C13T、A15G、A16C、A16G、A16T和G18T的一种或多种突变。在优选的实施方案中,核苷酸序列包含一种或多种选自A3T、C7A、C9A和A12G的突变。在一些实施方案中,噬菌体包含至少一个在天然存在的噬菌体中不存在的突变,例如所述一种或多种突变可包括至少一个在噬菌体P1.1、P9.1、P14.4、P100.1、P100A、P100D、P101A、P104A、P015、ATCC_C或ATCC_T中并非天然存在的突变。
噬菌体可包含与SEQ ID NO:5(CAACTGCGCCAACAGTCTCATCTGATCCGAATACGG)或其反向互补序列具有至少约95%、96%、97%、98%或99%序列同源性的核苷酸序列。SEQ IDNO:5是噬菌体P1.1基因3的子序列(SEQ ID NO:7的残基1886-3211)。该子序列可以被痤疮丙酸杆菌菌株B101.9和B66.8的原间隔序列3识别。所述核苷酸序列可包含对选自SEQ IDNO:5的A2、A3、C4、T5、G6、C7、G8、C9、C10、A11、A12、C13、A14、G15、T16和T18的一个或多个核苷酸的突变。在优选的实施方案中,核苷酸序列包含对选自SEQ ID NO:5的A3、C7、A12和C13的一个或多个核苷酸的突变。核苷酸序列可包含对选自A3T、A3C、A3G、C4T、C7A、C7G、C9A、C10T、A12G、C13A、C13T、G15A、T16A、T16C、T16G和T18G的一种或多种突变。在优选的实施方案中,核苷酸序列包含选自A3C、A3G、C7A、A12G和C13A的一种或多种突变。在一些实施方案中,噬菌体包含至少一个在天然存在的噬菌体中不存在的突变,例如所述一种或多种突变可包括至少一个在噬菌体P1.1、P9.1、P14.4、P100.1、P100A、P100D、P101A、P104A、P015、ATCC_C或ATCC_T中并非天然存在的突变。
噬菌体可包含与SEQ ID NO:6(CAACGCAGCAATCTCAGAAGGCCACAACAAATTCGT)或其反向互补序列具有至少约95%、96%、97%、98%或99%序列同源性的核苷酸序列。SEQ IDNO:6是噬菌体P9.1基因7的子序列(SEQ ID NO:12的残基5610-6089)。该子序列可以被痤疮丙酸杆菌菌株B101.9和B66.8的原间隔序列4识别。核苷酸序列可包含对选自SEQ ID NO:6的A2、A3、G5、C6、A7、G8、C9、A11、T12、C13、T14、A16、A30、A31、T33、C34、G35和T36的一个或多个核苷酸的突变。在优选的实施方案中,核苷酸序列包含对选自SEQ ID NO:6的A3、C7、A12和C13的一个或多个核苷酸的突变。核苷酸序列可包含对选自C6A、C6T、A7G、G8T、T12C、A16G、A30G、A31G、T33G、C34A、G35A和T36A的一种或多种突变。在优选的实施方案中,核苷酸序列包含一种或多种选自C6A、G8T、T33G和G35A的突变。在一些实施方案中,噬菌体包含至少一个在天然存在的噬菌体中不存在的突变,例如所述一种或多种突变可包括至少一个在噬菌体P1.1、P9.1、P14.4、P100.1、P100A、P100D、P101A、P104A、P015、ATCC_C或ATCC_T中并非天然存在的突变。
在一些实施方案中,本发明涉及编码痤疮丙酸杆菌噬菌体的基因9(例如,SEQ IDNO:7的残基6453-6743或SEQ ID NO:12的残基6445-6735)的核苷酸序列,其中所述核苷酸序列与SEQ ID NO:1(GAAGTCTTCTGGGGTGCAGGGCATGTTGGCTGAGCG)或其反向互补序列具有至少约95%、96%、97%、98%或99%序列同源性。SEQ ID NO:1是噬菌体P9.1基因9的子序列(SEQ ID NO:12的残基6445-6735)。该子序列可以被痤疮丙酸杆菌菌株B101.9的原间隔序列1识别。在一些实施方案中,本发明涉及与SEQ ID NO:7的残基6453-6743或SEQ ID NO:12的残基6445-6735具有至少约95%、96%、97%、98%或99%序列同源性的核苷酸序列,例如其中所述核苷酸序列的子序列与SEQ ID NO:1具有至少约95%、96%、97%、98%或99%序列同源性。所述核苷酸序列可包含对选自SEQ ID NO:1的G1、A2、A3、G4、T5、C6、T7、T8、C9、T10、G11、G12、G13、G14、C17、G20、G21和G22的一个或多个核苷酸的突变。在优选的实施方案中,核苷酸序列包含对选自SEQ ID NO:1的A2、A3、T5、G11、G14和C17的一个或多个核苷酸的突变。核苷酸序列可包含相对于SEQ ID NO:1的一种或多种选自G1A、A2T、A2C、A3C、G4A、T5G、T7G、T8C、T10G、G11T、G13T、G14T、C17A、G20T、G21C、C22G和C22T的突变。在优选的实施方案中,核苷酸序列包含相对于SEQ ID NO:1的一种或多种选自A2T、T5G、G11T、G14T和C17A的突变。在一些实施方案中,核苷酸序列不存在于天然存在的生物中,例如核酸序列不存在于噬菌体P1.1、P9.1、P14.4、P100.1、P100A、P100D、P101A、P104A、P015、ATCC_C或ATCC_T中。在一些实施方案中,本发明涉及由基因9编码的蛋白质,其包含的氨基酸序列与SEQ ID NO:1的开放阅读框编码的氨基酸序列具有至少约95%、96%、97%、98%或99%序列同源性,其中所述蛋白质包含一种或多种对应于一种或多种前述核苷酸突变的氨基酸取代,例如其中每个核苷酸突变均为非同义突变。在一些实施方案中,本发明涉及包含与SEQ ID NO:10或SEQ ID NO:15中所列的氨基酸具有至少约95%、96%、97%、98%或99%序列同源性的氨基酸序列的蛋白质,其中所述蛋白质包含一种或多种对应于一种或多种前述核苷酸突变的氨基酸取代,例如其中每个核苷酸突变均为非同义突变。在一些实施方案中,所述蛋白质不存在于天然存在的生物中,例如所述蛋白质不存在于噬菌体P1.1、P9.1、P14.4、P100.1、P100A、P100D、P101A、P104A、P015、ATCC_C或ATCC_T中。在一些方面,本发明涉及包含前述核苷酸序列或蛋白质的细胞或噬菌体。
在一些实施方案中,本发明涉及编码痤疮丙酸杆菌噬菌体的基因9(例如,SEQ IDNO:7的残基6453-6743或SEQ ID NO:12的残基6445-6735)的核苷酸序列,其中所述核苷酸序列与SEQ ID NO:2(GAAGTCTTCTGGGGTGCAGTCTATGTTGGCTGAGCG)或其反向互补序列具有至少约95%、96%、97%、98%或99%序列同源性。SEQ ID NO:2是噬菌体P1.1基因9的子序列(SEQ ID NO:7的残基6453-6743)。该子序列可以被痤疮丙酸杆菌菌株B101.9的原间隔序列1识别。在一些实施方案中,本发明涉及与SEQ ID NO:7的残基6453-6743或SEQ ID NO:12的残基6445-6735具有至少约95%、96%、97%、98%或99%序列同源性的核苷酸序列,例如其中所述核苷酸序列的子序列与SEQ ID NO:2具有至少约95%、96%、97%、98%或99%序列同源性。核苷酸序列可包含对选自SEQ ID NO:2的G1、A2、A3、G4、T5、C6、T7、T8、C9、T10、G11、G12、G13、G14、C17、T20、C21和T22的一个或多个核苷酸的突变。在优选的实施方案中,核苷酸序列包含对选自SEQ ID NO:2的A2、A3、T5、G11、G14和C17的一个或多个核苷酸的突变。核苷酸序列可包含SEQ ID NO:2的选自G1A、A2T、A2C、A3C、G4A、T5G、T7G、T8C、T10G、G11T、G13T、G14T、C17A、T20G、C21G、T22G和T22C的一种或多种突变。在优选的实施方案中,核苷酸序列包含相对于SEQ ID NO:2的选自A2C和A3C的一种或多种突变。在一些实施方案中,核苷酸序列不存在于天然存在的生物中,例如核酸序列不存在于噬菌体P1.1、P9.1、P14.4、P100.1、P100A、P100D、P101A、P104A、P015、ATCC_C或ATCC_T中。在一些实施方案中,本发明涉及由基因9编码的蛋白质,其包含的氨基酸序列与SEQ ID NO:2的开放阅读框编码的氨基酸序列具有至少约95%、96%、97%、98%或99%序列同源性,其中所述蛋白质包含一种或多种对应于一种或多种前述核苷酸突变的氨基酸取代,例如其中每个核苷酸突变均为非同义突变。在一些实施方案中,本发明涉及包含与SEQ ID NO:10或SEQ ID NO:15中所列的氨基酸具有至少约95%、96%、97%、98%或99%序列同源性的氨基酸序列的蛋白质,其中所述蛋白质包含一种或多种对应于一种或多种前述核苷酸突变的氨基酸取代,例如其中每个核苷酸突变均为非同义突变。在一些实施方案中,所述蛋白质不存在于天然存在的生物中,例如所述蛋白质不存在于噬菌体P1.1、P9.1、P14.4、P100.1、P100A、P100D、P101A、P104A、P015、ATCC_C或ATCC_T中。在一些方面,本发明涉及包含前述核苷酸序列或蛋白质的细胞或噬菌体。
在一些实施方案中,本发明涉及编码痤疮丙酸杆菌噬菌体的基因16(例如,SEQ IDNO:7的残基12239-13399或SEQ ID NO:12的残基12238-13398)的核苷酸序列,其中所述核苷酸序列与SEQ ID NO:3(TAAGATTGAGTTGGCTGAGTCGGATGTGTTGCGGTT)或其反向互补序列具有至少约95%、96%、97%、98%或99%序列同源性。SEQ ID NO:3是噬菌体P1.1基因16的子序列(SEQ ID NO:7的残基12239-13399)。该子序列可以被痤疮丙酸杆菌菌株B66.8的原间隔序列1识别。在一些实施方案中,本发明涉及与SEQ ID NO:7的残基12239-13399或SEQ IDNO:12的残基12238-13398具有至少约95%、96%、97%、98%或99%序列同源性的核苷酸序列,例如其中所述核苷酸序列的子序列与SEQ ID NO:3具有至少约95%、96%、97%、98%或99%序列同源性。核苷酸序列可包含对选自SEQ ID NO:3的A2、A3、A5、T6、T7、G8、A9、T11、T12、G13、G14、T16、G19、T20、G23、T25、T30和G31的一个或多个核苷酸的突变。在优选的实施方案中,核苷酸序列包含对选自SEQ ID NO:3的T20、T30和G31的一个或多个核苷酸的突变。核苷酸序列可包含相对于SEQ ID NO:3的选自T7C、T16A、T16G、G19A、T20G、G23A、T25G、T30G和G31T的一种或多种突变。在优选的实施方案中,核苷酸序列包含相对于SEQ ID NO:3选自T20G、T30G和G31T的一种或多种突变。在一些实施方案中,核苷酸序列不存在于天然存在的生物中,例如核酸序列不存在于噬菌体P1.1、P9.1、P14.4、P100.1、P100A、P100D、P101A、P104A、P015、ATCC_C或ATCC_T中。在一些实施方案中,本发明涉及由基因16编码的蛋白质,其包含的氨基酸序列与SEQ ID NO:3的开放阅读框编码的氨基酸序列具有至少约95%、96%、97%、98%或99%序列同源性,其中所述蛋白质包含一种或多种对应于一种或多种前述核苷酸突变的氨基酸取代,例如其中每个核苷酸突变均为非同义突变。在一些实施方案中,本发明涉及包含与SEQ ID NO:11或SEQ ID NO:16中所列的氨基酸具有至少约95%、96%、97%、98%或99%序列同源性的氨基酸序列的蛋白质,其中所述蛋白质包含一种或多种对应于一种或多种前述核苷酸突变的氨基酸取代,例如其中每个核苷酸突变均为非同义突变。在一些实施方案中,所述蛋白质不存在于天然存在的生物中,例如所述蛋白质不存在于噬菌体P1.1、P9.1、P14.4、P100.1、P100A、P100D、P101A、P104A、P015、ATCC_C或ATCC_T中。在一些方面,本发明涉及包含前述核苷酸序列或蛋白质的细胞或噬菌体。
在一些实施方案中,本发明涉及编码痤疮丙酸杆菌噬菌体的基因3(例如,SEQ IDNO:7的残基1886-3211或SEQ ID NO:12的残基1881-3206)的核苷酸序列,其中所述核苷酸序列与SEQ ID NO:4(CAACTGCGCCAACAAACGCATCTGATCCGAATACGG)或其反向互补序列具有至少约95%、96%、97%、98%或99%序列同源性。SEQ ID NO:4是噬菌体P9.1基因3的子序列(SEQ ID NO:12的残基1881-3206)。该子序列可以被痤疮丙酸杆菌菌株B101.9和B66.8的原间隔序列3识别。在一些实施方案中,本发明涉及与SEQ ID NO:7的残基1886-3211或SEQ IDNO:12的残基1881-3206具有至少约95%、96%、97%、98%或99%序列同源性的核苷酸序列,例如其中所述核苷酸序列的子序列与SEQ ID NO:4的反向互补序列具有至少约95%、96%、97%、98%或99%序列同源性。所述核苷酸序列可包含对选自SEQ ID NO:4的A2、A3、C4、T5、G6、C7、G8、C9、C10、A11、A12、C13、A14、A15、A16和G18的一个或多个核苷酸的突变。在优选的实施方案中,核苷酸序列包含对选自SEQ ID NO:4的A3、C7、C9和A12的一个或多个核苷酸的突变。核苷酸序列可包含相对于SEQ ID NO:4的选自A3T、A3C、A3G、C4T、C7A、C7G、C9A、C10T、A12G、C13A、C13T、A15G、A16C、A16G、A16T和G18T的一种或多种突变。在优选的实施方案中,核苷酸序列包含相对于SEQ ID NO:4的一种或多种选自A3T、C7A、C9A和A12G的突变。在一些实施方案中,核苷酸序列不存在于天然存在的生物中,例如核酸序列不存在于噬菌体P1.1、P9.1、P14.4、P100.1、P100A、P100D、P101A、P104A、P015、ATCC_C或ATCC_T中。在一些实施方案中,本发明涉及由基因3编码的蛋白质,其包含的氨基酸序列与SEQ ID NO:4的开放阅读框编码的氨基酸序列具有至少约95%、96%、97%、98%或99%序列同源性,其中所述蛋白质包含一种或多种对应于一种或多种前述核苷酸突变的氨基酸取代,例如其中每个核苷酸突变均为非同义突变。在一些实施方案中,本发明涉及包含与SEQ ID NO:8或SEQID NO:13中所列的氨基酸具有至少约95%、96%、97%、98%或99%序列同源性的氨基酸序列的蛋白质,其中所述蛋白质包含一种或多种对应于一种或多种前述核苷酸突变的氨基酸取代,例如其中每个核苷酸突变均为非同义突变。在一些实施方案中,所述蛋白质不存在于天然存在的生物中,例如所述蛋白质不存在于噬菌体P1.1、P9.1、P14.4、P100.1、P100A、P100D、P101A、P104A、P015、ATCC_C或ATCC_T中。在一些方面,本发明涉及包含前述核苷酸序列或蛋白质的细胞或噬菌体。
在一些实施方案中,本发明涉及编码痤疮丙酸杆菌噬菌体的基因3(例如,SEQ IDNO:7的残基1886-3211或SEQ ID NO:12的残基1881-3206)的核苷酸序列,其中所述核苷酸序列与SEQ ID NO:5(CAACTGCGCCAACAGTCTCATCTGATCCGAATACGG)或其反向互补序列具有至少约95%、96%、97%、98%或99%序列同源性。SEQ ID NO:5是噬菌体P1.1基因3的子序列(SEQ ID NO:7的残基1886-3211)。该子序列可以被痤疮丙酸杆菌菌株B101.9和B66.8的原间隔序列3识别。在一些实施方案中,本发明涉及与SEQ ID NO:7的残基1886-3211或SEQ IDNO:12的残基1881-3206具有至少约95%、96%、97%、98%或99%序列同源性的核苷酸序列,例如其中所述核苷酸序列的子序列与SEQ ID NO:5的反向互补序列具有至少约95%、96%、97%、98%或99%序列同源性。所述核苷酸序列可包含对选自SEQ ID NO:5的A2、A3、C4、T5、G6、C7、G8、C9、C10、A11、A12、C13、A14、G15、T16和T18的一个或多个核苷酸的突变。在优选的实施方案中,核苷酸序列包含对选自SEQ ID NO:5的A3、C7、A12和C13的一个或多个核苷酸的突变。核苷酸序列可包含相对于SEQ ID NO:5的选自A3T、A3C、A3G、C4T、C7A、C7G、C9A、C10T、A12G、C13A、C13T、G15A、T16A、T16C、T16G和T18G的一种或多种突变。在优选的实施方案中,核苷酸序列包含相对于SEQ ID NO:5的一种或多种选自A3C、A3G、C7A、A12G和C13A的突变。在一些实施方案中,核苷酸序列不存在于天然存在的生物中,例如核酸序列不存在于噬菌体P1.1、P9.1、P14.4、P100.1、P100A、P100D、P101A、P104A、P015、ATCC_C或ATCC_T中。在一些实施方案中,本发明涉及由基因3编码的蛋白质,其包含的氨基酸序列与SEQ IDNO:5的开放阅读框编码的氨基酸序列具有至少约95%、96%、97%、98%或99%序列同源性,其中所述蛋白质包含一种或多种对应于一种或多种前述核苷酸突变的氨基酸取代,例如其中每个核苷酸突变均为非同义突变。在一些实施方案中,本发明涉及包含与SEQ IDNO:8或SEQ ID NO:13中所列的氨基酸具有至少约95%、96%、97%、98%或99%序列同源性的氨基酸序列的蛋白质,其中所述蛋白质包含一种或多种对应于一种或多种前述核苷酸突变的氨基酸取代,例如其中每个核苷酸突变均为非同义突变。在一些实施方案中,所述蛋白质不存在于天然存在的生物中,例如所述蛋白质不存在于噬菌体P1.1、P9.1、P14.4、P100.1、P100A、P100D、P101A、P104A、P015、ATCC_C或ATCC_T中。在一些方面,本发明涉及包含前述核苷酸序列或蛋白质的细胞或噬菌体。
在一些实施方案中,本发明涉及编码痤疮丙酸杆菌噬菌体的基因7(例如,SEQ IDNO:7的残基5618-6097或SEQ ID NO:12的残基5610-6089)的核苷酸序列,其中所述核苷酸序列与SEQ ID NO:6(CAACGCAGCAATCTCAGAAGGCCACAACAAATTCGT)或其反向互补序列具有至少约95%、96%、97%、98%或99%序列同源性。SEQ ID NO:6是噬菌体P9.1基因7的子序列(SEQ ID NO:12的5610-6089)。该子序列可以被痤疮丙酸杆菌菌株B101.9和B66.8的原间隔序列4识别。在一些实施方案中,本发明涉及与SEQ ID NO:7的残基5618-6097或SEQ ID NO:12的残基5610-6089具有至少约95%、96%、97%、98%或99%序列同源性的核苷酸序列,例如其中所述核苷酸序列的子序列与SEQ ID NO:6的反向互补序列具有至少约95%、96%、97%、98%或99%序列同源性。核苷酸序列可包含对选自SEQ ID NO:6的A2、A3、G5、C6、A7、G8、C9、A11、T12、C13、T14、A16、A30、A31、T33、C34、G35和T36的一个或多个核苷酸的突变。在优选的实施方案中,核苷酸序列包含对选自SEQ ID NO:6的A3、C7、A12和C13的一个或多个核苷酸的突变。核苷酸序列可包含相对于SEQ ID NO:6的选自C6A、C6T、A7G、G8T、T12C、A16G、A30G、A31G、T33G、C34A、G35A和T36A的一种或多种突变。在优选的实施方案中,核苷酸序列包含相对于SEQ ID NO:6的一种或多种选自C6A、G8T、T33G和G35A的突变。在一些实施方案中,核苷酸序列不存在于天然存在的生物中,例如核酸序列不存在于噬菌体P1.1、P9.1、P14.4、P100.1、P100A、P100D、P101A、P104A、P015、ATCC_C或ATCC_T中。在一些实施方案中,本发明涉及由基因7编码的蛋白质,其包含的氨基酸序列与SEQ ID NO:6的开放阅读框编码的氨基酸序列具有至少约95%、96%、97%、98%或99%序列同源性,其中所述蛋白质包含一种或多种对应于一种或多种前述核苷酸突变的氨基酸取代,例如其中每个核苷酸突变均为非同义突变。在一些实施方案中,本发明涉及包含与SEQ ID NO:9或SEQ ID NO:14中所列的氨基酸具有至少约95%、96%、97%、98%或99%序列同源性的氨基酸序列的蛋白质,其中所述蛋白质包含一种或多种对应于一种或多种前述核苷酸突变的突变,例如其中每个核苷酸突变均为非同义突变。在一些实施方案中,所述蛋白质不存在于天然存在的生物中,例如所述蛋白质不存在于噬菌体P1.1、P9.1、P14.4、P100.1、P100A、P100D、P101A、P104A、P015、ATCC_C或ATCC_T中。在一些方面,本发明涉及包含前述核苷酸序列或蛋白质的细胞或噬菌体。
在一些实施方案中,本公开的噬菌体与一种或多种其它噬菌体(噬菌体混合物)组合使用。噬菌体的组合可以靶向痤疮丙酸杆菌的相同菌株或不同菌株。可以同时施加噬菌体混合物-即,它们可以在相同时间施加(例如,在相同的施加中或甚至在相同的组合物中),或者可以在时间上隔开的单独施加中施加,使其在相同时间有效。噬菌体可以作为单次施加、定期施加或作为连续施加而施加。
噬菌体或噬菌体组合可以与一种或多种其它抗微生物剂组合使用。抗微生物剂可包括已知的抗痤疮剂,诸如类视黄醇、过氧化苯甲酰或抗生素,或新型抗微生物剂,诸如颗粒溶素或痤疮丙酸杆菌噬菌体内溶素蛋白。在一些实施方案中,抗生素或抗体组合选自青霉素(penicillin)、头孢菌素(cephalosporin)、碳青霉烯(carbapenem)、氨基糖苷、磺胺、喹诺酮(quinolone)、大环内酯类、四环素、脂肽和噁唑烷酮(oxazolidinone)。
抗生素是指一类药剂,但不限于氨基糖苷类抗生素、糖肽类抗生素、大环内酯类抗生素及其组合。示例性抗生素可以对革兰氏阴性细菌具有活性,并且可以对革兰氏阳性和革兰氏阴性细菌都具有活性。抗生素的非限制性实例包括红霉素(erythromycin)、正泰霉素(garamycin)、庆大霉素(gentamicin)、卡那霉素(kanamycin)、新霉素(neomycin)、奈替米星(netilmicin)、巴龙霉素(paramomycin)、妥布霉素(tobramycin)、万古霉素(vancomycin)及其类似物以及其组合。有多种抗生素可用于本发明的方法中。在一些实施方案中,抗生素或抗体组合选自青霉素、头孢菌素、碳青霉烯、氨基糖苷、磺胺、喹诺酮、大环内酯类、四环素、脂肽和噁唑烷酮。在受试者对一类抗生素诸如头孢菌素及其组合已知或疑似过敏的情况下,可以使用合适的抗生素。
在一些实施方案中,可以基于受试者的细菌微生物群的抗性特征来特异性选择抗生素或抗生素的组合。
在一些实施方案中,抗生素或抗生素混合物(包含至少两种抗生素)选自阿莫西林(amoxicillin)、氨苄青霉素(ampicillin)、巴卡西林(bacampicillin)、羧苄青霉素(carbenicillin)、氯洒西林(cloxacillin)、双氯西林(dicloxacillin)、氟氯西林(flucloxacillin)、美洛西林(mezlocillin)、萘夫西林(nafcillin)、苯唑西林(oxacillin)、青霉素G、青霉素V、哌拉西林(Piperacillin)、匹氨西林(Pivampicillin)、匹美西林(Pivmecillinam)、替卡西林(Ticarcillin)、头孢乙腈(cefacetrile)、头孢羟氨苄(cefadroxil)、头孢氨苄(cephalexin)、头孢来星(cefaloglycin)、头孢洛宁(cefalonium)、头孢噻啶(cefaloridine)、头孢噻吩(cefalotin)、头孢孟多(cefamandole)、头孢匹林(cefapirin)、头孢西丁(cefatoxin)、头孢曲秦(cefatrizine)、头孢氮氟(cefazaflur)、头孢氨苄(cephalexin)、头孢西酮(cefazedone)、头孢唑啉(cefazolin)、头孢吡肟(cefepime)、头孢拉定(cefradine)、头孢沙定(cefroxadine)、头孢替唑(ceftezole)、头孢克洛(cefaclor)、头孢尼西(cefonicid)、头孢丙烯(cefprozil)、头孢呋辛(cefuroxime)、头孢唑南(cefuzonam)、头孢甲氧氰唑(cefinetazole)、头孢替坦(cefotetan)、头孢西丁(cefoxitin)、氯碳头孢(loracarbef)、头孢拉宗(cefbuperazone)、头孢甲氧氰唑(cefinetazole)、头孢米诺(cefminox)、头孢替坦(cefotetan)、头孢西丁(cefoxitin)、头孢卡品(cefcapene)、头孢达肟(cefdaloxime)、头孢地尼(cefdinir)、头孢妥仑(cefditoren)、头孢他美(cefetamet)、头孢克肟(cefixime)、头孢甲肟(cefinenoxime)、头孢地嗪(cefodizime)、头孢噻肟(cefotaxime)、头孢维星(cefovecin)、头孢咪唑(cefpimizole)、头孢泊肟(cefpodoxime)、头孢特仑(cefteram)、头孢布烯(ceftibuten)、头孢噻呋(ceftiofur)、头孢噻林(ceftiolene)、头孢唑肟(ceftizoxime)、头孢曲松(ceftriaxone)、头孢哌酮(cefoperazone)、头孢他啶(ceftazidime)、拉氧头孢(latamoxef)、头孢克定(cefclidine)、头孢吡肟(cefepime)、头孢瑞南(cefluprenam)、头孢噻利(cefoselis)、头孢唑兰(cefozopran)、头孢匹罗(cefpirome)、头孢喹肟(cefquinome)、氟氧头孢(flomoxef)、头孢比普(ceftobiprole)、头孢洛林(ceftaroline)、亚胺培南(imipenem)、美罗培南(meropenem)、厄他培南(ertapenem)、多利培南(doripenem)、帕尼培南(panipenem)、倍他米隆(betamipron)、比阿培南(biapenem)、阿祖培南(razupenem)、阿米卡星(amikacin)、阿贝卡星(arbekacin)、庆大霉素、卡那霉素、新霉素、奈替米星、巴龙霉素、红链霉素(rhodostreptomycin)、链霉素(streptomycin)、妥布霉素(tobramycin)、安普霉素(apramycin)、弗氏菌丝素(framycetin)、核糖霉素(ribostamycin)、卡那霉素B(bekanamycin)、地贝卡星(dibekacin)、妥布霉素(tobramycin)、壮观霉素(spectinomycin)、潮霉素B(hygromycinB)、硫酸巴龙霉素(paromomycinsulfate)、西索米星(sisomicin)、异帕米星(isepamicin)、威大霉素(verdamicin)、阿司米星(astromicin)、柳氮磺胺吡啶(sulfasalazine)、磺胺甲噁唑(sulfamethoxazole)、磺胺甲噻二唑(sulfamethizole)、磺胺异噁唑(sulfisoxazole)、氟喹诺酮(fluoroquinolone)、酮内酯(ketolide)、头孢比普(ceftobiprole)、氟甲喹(flumequine)、萘啶酸(nalidixicacid)、噁喹酸(oxolinicacid)、吡咯米酸(piromidicacid)、吡哌酸(pipemidic acid)、罗索沙星(rosoxacin)、环丙沙星(ciprofloxacin)、依诺沙星(enoxacin)、洛美沙星(lomefloxacin)、那氟沙星(nadifloxacin)、诺氟沙星(norfloxacin)、培氟沙星(pefloxacin)、芦氟沙星(rufloxacin)、巴洛沙星(balofloxacin)、加替沙星(gatifloxacin)、格帕沙星(grepafloxacin)、左氧氟沙星(levofloxacin)、莫西沙星(moxifloxacin)、帕珠沙星(pazufloxacin)、司帕沙星(sparfloxacin)、替马沙星(temafloxacin)、托氟沙星(tosufloxacin)、克林沙星(clinafloxacin)、吉米沙星(gemifloxacin)、西他沙星(sitafloxacin)、曲伐沙星(trovafloxacin)、普卢利沙星(prulifloxacin)、阿奇霉素(azithromycin)、红霉素、克拉霉素(clarithromycin)、地红霉素(dirithromycin)、罗红霉素(roxithromycin)、泰利霉素(telithromycin)、地美环素(demeclocycline)、强力霉素(doxycycline)、米诺环素(minocycline)、土霉素(oxytetracycline)、四环素、利奈唑胺(linezolid)、克林霉素(clindamycin)、甲硝唑(metronidazole)、万古霉素、利福布汀(rifabutin)、利福平(rifampin)、呋喃妥因(nitrofurantoin)、氯霉素(chloramphenicol)及其组合。
在一些实施方案中,组合物包含消除半衰期小于20小时的抗生素。在一些实施方案中,组合物包含消除半衰期为约1至12小时的抗生素。以下是一些半衰期为约1至12小时的抗生素的实例,可从中选择抗生素或抗生素的组合:头孢羟氨苄、头孢唑啉、头孢氨苄、头孢噻吩(cephalothin)、头孢匹林(cephapirin)、cephacelor、头孢丙烯(cephprozil)、头孢拉定(cephadrine)、头孢孟多(cefamandole)、头孢尼西(cefonicid)、头孢雷特(ceforanide)、头孢呋辛(cefuroxime)、头孢克肟(cefixime)、头孢哌酮(cefoperazone)、头孢噻肟(cefotaxime)、头孢泊肟(cefpodoxime)、头孢他定(ceftaxidime)、头孢布烯(ceftibuten)、头孢唑肟(ceftizoxime)、头孢曲松(ceftriaxone)、头孢吡肟(cefepime)、头孢美唑(cefmetazole)、头孢替坦、头孢西丁、氯碳头孢、亚胺培南、红霉素(以及红霉素盐,诸如依托红霉素、琥乙红霉素、葡庚糖酸红霉素、乳糖酸红霉素、硬脂酸红霉素)、阿奇霉素、克拉霉素(clarithromycoin)、地红霉素、依托红霉素(troleanomycin)、青霉素V、青霉素盐和复合物、甲氧西林(methicillin)、萘夫西林(nafcillin)、苯唑西林、氯洒西林、双氯西林、阿莫西林、阿莫西林和克拉维酸钾(clavulanatepotassium)、氨苄青霉素、巴卡西林、羧苄西林茚满钠(和其它羧苄青霉素盐)美洛西林、哌拉西林、哌拉西林和他佐巴坦(taxobactam)、替卡西林、替卡西林和克拉维酸钾、克林霉素、万古霉素、新生霉素(novobiocin)、氨基水杨酸、卷曲霉素(capreomycin)、环丝氨酸(cycloserine)、乙胺丁醇盐酸盐和其它盐、乙硫异烟胺(ethionamide)和异烟肼(isoniazid)、环丙沙星、左氧氟沙星、洛美沙星、萘啶酸、诺氟沙星、氧氟沙星(ofloxacin)、司帕沙星、磺胺西汀(sulfacytine)、磺胺甲嘧啶(sulfamerazine)、磺胺二甲嘧啶(sulfamethazine)、sulfamethixole、柳氮磺胺吡啶、磺胺异噁唑(sulfisoxazole)、sulfapyrizine、磺胺嘧啶(sulfadiazine)、磺胺甲噁唑(sulfinethoxazole)、磺胺吡啶(sulfapyridine)、甲硝唑、乌洛托品(methenamine)、磷霉素(fosfomycin)、呋喃妥因(nitrofurantoin)、甲氧苄啶(trimethoprim)、氯法齐明(clofazimine)、复方磺胺甲噁唑(co-triamoxazole)、喷他脒(pentamidine)和三甲曲沙(trimetrexate)。
在一些实施方案中,抗生素选自氨基糖苷类抗生素、糖肽类抗生素、大环内酯类抗生素及其组合。在一些实施方案中,抗生素选自红霉素、庆大霉素、妥布霉素、万古霉素及其组合。在一些实施方案中,抗生素是庆大霉素。
抗生素或至少两种抗生素的组合(有时称为抗生素混合物)本身或在药物组合物中施用给受试者,在药物组合物中抗生素与合适的载体或赋形剂混合。
IV.调配物、剂量和施用
本发明的痤疮丙酸杆菌噬菌体可以按下述比例配制成组合物,其比例以干重表示为至少0.0001%,尤其是比例为0.0001%至30%,尤其是比例为0.001%至20%并且更特别地相对于含有痤疮丙酸杆菌噬菌体的组合物的总重量,其比例按重量计为0.01%至15%,尤其是按重量计为0.1%至10%和按重量计为1%至5%。
本发明的组合物和方法可用于治疗有需要的个体。在某些实施方案中,个体为哺乳动物诸如人或非人类哺乳动物。当施用给动物,诸如人时,所述组合物或噬菌体优选作为包含例如本发明的噬菌体和药学上可接受的载体的药物组合物施用。
药学上可接受的载体是本领域公知的,并且包括(例如)水溶液(诸如水或生理缓冲盐水)或其它溶剂或媒介物(诸如二醇、甘油、油(诸如橄榄油)或可注射的有机酯)。在一个优选的实施方案中,当此类药物组合物用于人类施用时,该水溶液是无热原的,或基本上无热原的。可以选择赋形剂(例如)以实现药剂的延迟释放或选择性地靶向一种或多种细胞、组织或器官。药物组合物可以呈诸如片剂、胶囊剂(包括分散型胶囊和明胶胶囊)、粒剂、粉剂、糖浆剂、栓剂、注射剂等剂量单位形式。组合物也可以存在于透皮递送系统中,例如皮肤贴剂中。组合物也可以存在于适于局部施用的溶液中,例如滴眼剂中。
药学上可接受的载体可含有生理上可接受的药剂,其起到(例如)稳定或增加本发明噬菌体的吸收的作用。此类生理上可接受的药剂包括(例如)碳水化合物(诸如葡萄糖、蔗糖或葡聚糖)、抗氧化剂(诸如抗坏血酸或谷胱甘肽)、螯合剂、低分子量蛋白质或其它稳定剂或赋形剂。药学上可接受的载体(包括生理上可接受的药剂)的选择取决于(例如)组合物的施用途径。药物组合物(制剂)也可以是其中可以掺入(例如)本发明的噬菌体的脂质体或其它聚合物基质。例如包含磷脂或其它脂质的脂质体是相对容易制备和施用的无毒、生理上可接受和可代谢的载体。
短语“药学上可接受的”在本文中用于指那些化合物、材料、组合物和/或剂型在合理的医学判断范围内,适合接触人类和动物的组织使用而无过度毒性、刺激、过敏响应或其它问题或并发症,与合理的效益/风险比相称。
如本文所用的术语“药学上可接受的载体”意指药学上可接受的材料、组合物或媒介物,诸如液体或固体填料、稀释剂、赋形剂、溶剂或包封材料。在与调配物的其它成分相容并且不损伤患者的意义上,每种载体必须是“可接受的”。可用作药学上可接受的载体的材料的一些实例包括:(1)糖,诸如乳糖、葡萄糖和蔗糖;(2)淀粉,诸如玉米淀粉和马铃薯淀粉;(3)纤维素及其衍生物,诸如羧甲基纤维素钠、乙基纤维素和乙酸纤维素;(4)粉末状黄蓍胶;(5)麦芽;(6)明胶;(7)滑石;(8)赋形剂,诸如可可脂和栓剂蜡;(9)油,诸如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和大豆油;(10)二醇,诸如丙二醇;(11)多元醇,如甘油、山梨糖醇、甘露醇和聚乙二醇;(12)酯,诸如油酸乙酯和月桂酸乙酯;(13)琼脂;(14)缓冲剂,诸如氢氧化镁和氢氧化铝;(15)海藻酸;(16)无热原水;(17)等渗盐水;(18)林格氏溶液;(19)乙醇;(20)磷酸盐缓冲溶液;和(21)药物调配物中使用的其它无毒相容物质。
药物组合物(制剂)可以通过许多施用途径中的任一种施用于受试者,所述施用途径包括(例如)口服(例如,施加于舌头的呈水性或非水性溶液或混悬液的灌服剂(drenches)、片剂、胶囊剂(包括分散型胶囊和明胶胶囊)、药丸剂、粉剂、粒剂、糊剂);通过口腔黏膜吸收(例如舌下);经肛门、经直肠或经阴道(例如,作为子宫托、乳膏剂或泡沫剂);肠胃外(包括肌内、静脉内、皮下或鞘内,例如作为无菌溶液剂或混悬剂);经鼻;腹膜内;皮下;经皮(例如作为施加于皮肤的贴剂);和局部(例如,作为施加于皮肤的乳膏剂、软膏剂或喷雾剂,或作为滴眼剂)。噬菌体也可配制用于吸入。在某些实施方案中,噬菌体可简单地溶解或悬浮在无菌水中。适当施用途径和适于其的组合物的详情可以在例如美国专利第6,110,973、5,763,493、5,731,000、5,541,231、5,427,798、5,358,970和4,172,896号,以及其中引用的专利中发现。
制剂可以方便地以单位剂型存在,并且可以通过药学领域熟知的任何方法制备。可以与载体材料组合产生单一剂型的活性成分的量将根据治疗的宿主、特定施用方式而变化。可以与载体材料组合产生单一剂型的活性成分的量通常将是产生疗效的噬菌体的量。通常,以百分之百的百分比计,该量的范围将为活性成分的约1%至约99%,优选约5%至约70%,最优选约10%至约30%。
制备这些调配物或组合物的方法包括使本发明的噬菌体与载体和任选一种或多种辅助成分缔合的步骤。一般而言,调配物通过使本发明的噬菌体与液体载体或细碎固体载体或两者均匀且紧密地缔合,然后,如果需要,使产品成形而制备。
在本发明的一些实施方案中,适用于本发明的噬菌体可以口服、局部或肠胃外施用,且尤其是局部施用。
用于局部或透皮施用的剂型包括粉剂、喷雾剂、软膏剂、糊剂、乳膏剂、洗剂、凝胶剂、溶液、贴剂和吸入剂。噬菌体可以在无菌条件下与药学上可接受的载体以及可能需要的任何防腐剂、缓冲剂或推进剂混合。
除了噬菌体外,软膏剂、糊剂、乳膏剂和凝胶剂还可以含有赋形剂,诸如动植物脂肪、油、蜡、石蜡、淀粉、黄蓍胶、纤维素衍生物、聚乙二醇、硅氧烷、膨润土、硅酸、滑石和氧化锌,或其混合物。
下面描述本发明一些实施方案的局部调配物的各种组成部分的示例特性。
媒介物
适合用于本发明调配物/组合物的局部媒介物和载体组分是化妆品和药物领域中公知的,并且包括此类媒介物(或媒介物组分)如水;有机溶剂诸如醇(特别是易于从皮肤蒸发的低级醇诸如乙醇)、二醇(诸如丙二醇、丁二醇和甘油(丙三醇))、脂肪醇(诸如羊毛脂);水和有机溶剂(诸如水和醇)的混合物,以及有机溶剂诸如醇和甘油的混合物(任选也与水混合);基于脂质的材料,诸如脂肪酸、酰基甘油(包括油,诸如矿物油和天然或合成来源的脂肪)、磷酸甘油酯、鞘脂和蜡;基于蛋白质的材料,诸如胶原蛋白和明胶;基于硅氧烷的材料(非挥发性和挥发性),诸如环甲硅油、聚二甲基硅氧烷醇、聚二甲基硅氧烷和聚二甲基硅氧烷共聚醇;基于碳氢化合物的材料,诸如凡士林和角鲨烷;适用于皮肤施用的其它媒介物和媒介物组分,以及如上所鉴定的或本领域已知的局部媒介物组分的混合物。
在一个实施方案中,本发明的组合物是水包油乳液。适用于配制本发明组合物的液体包括水和可与水混溶的溶剂,诸如二醇(例如乙二醇、丁二醇、异戊二烯二醇、丙二醇)、甘油、液体多元醇、二甲亚砜和异丙醇。可以存在一种或多种水性媒介物。
在一些实施方案中,调配物不含甲醇、乙醇、丙醇或丁醇。
表面活性剂和乳化剂
许多局部调配物含有化学乳液,其使用表面活性成分(乳化剂和表面活性剂)将不同的化学品分散在特定溶剂体系中。例如,大多数类脂(油性或脂肪)或亲脂性成分不能均匀地分散在水性溶剂中,除非它们先与乳化剂结合,形成含有亲脂性内部和亲水性外部的微观水溶性结构(液滴),产生水包油乳液。为了可溶于水性介质,分子必须是极性的或带电荷的,以便有利地与也是极性的水分子相互作用。类似地,为了将水溶性极性或带电成分溶解在主要基于脂质或油的溶剂中,通常使用乳化剂,其形成稳定结构,在结构内部含有亲水性组分,而外部是亲脂性的,使其可以溶解在亲脂性溶剂中形成油包水乳液。众所周知,可通过添加盐或其它带电成分而使此类乳液去稳定化,所述盐或其它带电成分可与乳液液滴内乳化剂的极性或带电部分相互作用。乳液去稳定化导致水性和亲脂性成分分成两层,可能破坏局部产品的商业价值。
适用于本发明的表面活性剂可以是离子型或非离子的型。这些包括但不限于:鲸蜡醇、聚山梨醇酯(聚山梨醇酯20、聚山梨醇酯40、聚山梨醇酯60、聚山梨醇酯80)、硬脂醇聚醚-10(Brij76)、十二烷基硫酸钠(月桂基硫酸钠)、月桂基二甲基氧化胺、鲸蜡基三甲基溴化铵(CTAB)、聚乙氧基化醇、聚氧乙烯脱水山梨糖醇、辛苯聚醇、N,N-二甲基十二烷基胺-N-氧化物、十六烷基三甲基溴化铵(HTAB)、聚氧乙烯10月桂基醚、胆盐(诸如脱氧胆酸钠或胆酸钠)、聚氧乙烯蓖麻油、壬基酚聚氧乙烯醚、环糊精、卵磷脂、聚二甲基硅氧烷共聚醇、月桂酰胺DEA、椰油酰胺DEA、椰油酰胺MEA、油基甜菜碱、椰油酰胺丙基甜菜碱、椰油酰胺丙基磷脂酰PG-二甲基氯化铵、磷酸二鲸蜡酯(双十六烷基磷酸)、鲸蜡硬脂醇聚醚-10磷酸酯、甲基苯扎氯铵、磷酸二鲸蜡酯、鲸蜡醇聚醚-10磷酸(鲸蜡醇聚醚-10是鲸蜡醇的聚乙二醇醚,其中n的平均值为10;鲸蜡醇聚醚-10磷酸是鲸蜡醇聚醚-10的磷酸酯混合物)、鲸蜡醇聚醚-20、BrijS10(聚乙二醇十八烷基醚,平均Mn~711)和泊洛沙姆(包括但不限于泊洛沙姆188(HO(C2H4O)a(CH(CH3)CH2O)b(C2H4O)aH,平均分子量为8400)和泊洛沙姆407(HO(C2H4O)a(CH(CH3)CH2O)b(C2H4O)aH,其中a约为101而b为约56))。根据本发明,也可以使用此类表面活性剂的适当组合或混合物。许多这些表面活性剂也可用作本发明调配物中的乳化剂。
用于本发明调配物中的其它合适的乳化剂包括但不限于山崳基三甲基硫酸甲酯铵-鲸蜡硬脂醇、非离子乳化剂如乳化蜡、聚氧乙烯油基醚、PEG-40硬脂酸酯、十六十八醇(鲸蜡硬脂醇)、鲸蜡硬脂醇聚醚-12、鲸蜡硬脂醇聚醚-20、鲸蜡硬脂醇聚醚-30、鲸蜡硬脂醇聚醚醇、鲸蜡醇聚醚-20(鲸蜡醇聚醚-20是鲸蜡醇的聚乙二醇醚,其中n的平均值为20)、油酸、油醇、甘油硬脂酸酯、PEG-75硬脂酸酯、PEG-100硬脂酸酯和PEG-100硬脂酸酯、神经酰胺2、神经酰胺3、硬脂酸、胆固醇、硬脂醇聚醚-2和硬脂醇聚醚-20,或其组合/混合物,以及阳离子乳化剂如硬脂酰胺丙基二甲胺和山崳基三甲基硫酸甲酯铵,或其组合/混合物。
保湿剂、润肤剂和湿润剂
一般的局部产品,尤其是化妆品产品,最重要的一个方面是消费者对产品美容品质的感知。例如,虽然白凡士林是一种极好的保湿剂和皮肤保护剂,但它很少单独使用,特别是很少用于面部,因为它油腻、粘稠、不易擦到皮肤上并且可能会弄脏衣物。消费者高度重视精美高雅且在皮肤上具有可接受的触感和性能的产品。适用于本发明调配物的保湿剂包括但不限于乳酸和其它羟基酸及其盐、甘油、丙二醇、丁二醇、PCA钠、透明质酸钠、碳蜡(Carbowax)200、碳蜡400和碳蜡800。适用于本发明调配物的润肤剂或湿润剂包括但不限于泛醇、棕榈酸鲸腊酯、甘油(丙三醇)、PPG-15硬脂醇醚、羊毛脂醇、羊毛脂、羊毛脂衍生物、胆固醇、凡士林、异硬脂基新戊酸酯、硬脂酸辛酯、矿物油、异鲸蜡醇硬脂酸酯、肉豆蔻醇肉豆蔻酸酯、辛基十二烷醇、棕榈酸2-乙基己酯(棕榈酸辛酯)、聚二甲基硅氧烷、苯基三甲基聚硅氧烷、环甲硅油、C12-C15烷基苯甲酸酯、聚二甲基硅氧烷醇、丙二醇、大花可可树籽脂、神经酰胺(例如神经酰胺2或神经酰胺3)、羟丙基双棕榈酰胺MEA、羟丙基双月桂酰胺MEA、羟丙基双异硬脂酰胺MEA、1,3-双(N-2-(羟乙基)硬脂酰氨基)-2-羟基丙烷、双羟乙基生育酚琥珀酰胺基羟基丙烷、尿素、芦荟、尿囊素、甘草次酸、红花油、油醇、油酸、硬脂酸、二辛酸酯/二癸酸酯、癸二酸二乙酯、异硬脂醇、戊二醇、异壬酸异壬酯和1,3-双(N-2-(羟乙基)棕榈酰氨基)-2-羟基丙烷。另外,根据本发明可以使用这些保湿剂和润肤剂中任何一种的适当组合和混合物。
防腐剂和抗氧化剂
该组合物还可包括适于改善所施加的调配物的稳定性或有效性的组分。
适用于本发明的防腐剂包括但不限于:脲,诸如咪唑烷基脲和重氮烷基咪唑脲;苯氧乙醇;对羟基苯甲酸甲酯钠、对羟基苯甲酸甲酯、对羟基苯甲酸乙酯和对羟基苯甲酸丙酯;山梨酸钾;苯甲酸钠;山梨酸;苯甲酸;甲醛;柠檬酸;柠檬酸钠;二氧化氯;季铵化合物,诸如苯扎氯铵、苄索氯铵、溴棕三甲铵(cetrimide)、地喹氯铵(dequalinium chloride)和氯化十六烷基吡啶;汞类试剂,诸如硝酸苯汞、醋酸苯汞和硫柳汞;吡罗克酮乙醇胺(piroctoneolamine);葡萄籽油;和醇类试剂,例如氯丁醇、二氯苄醇、苯乙醇和苄醇。
合适的抗氧化剂包括但不限于抗坏血酸及其酯、亚硫酸氢钠、丁基化羟基甲苯、丁基化羟基苯甲醚、生育酚、生育酚乙酸酯、抗坏血酸钠/抗坏血酸、抗坏血酸棕榈酸酯、没食子酸丙酯和螯合剂如EDTA(例如,EDTA二钠)、柠檬酸和柠檬酸钠。
在一些实施方案中,抗氧化剂或防腐剂包含(3-(4-氯苯氧基)-2-羟丙基)氨基甲酸酯。
在一些实施方案中,本发明的抗氧化剂或防腐剂还可以用作例如保湿剂或润肤剂。
另外,这些防腐剂或抗氧化剂的组合或混合物也可用于本发明的调配物中。
适合掺入本发明组合物中的其它组成部分包括但不限于:皮肤保护剂、吸附剂、缓和剂、润肤剂、保湿剂、缓释材料、增溶剂、皮肤渗透剂、皮肤舒缓剂、除臭剂、止汗剂、防晒剂、防晒鞣剂、维生素、头发调理剂、抗刺激剂、抗衰老剂、研磨剂、吸收剂、抗结块剂、抗静电剂、收敛剂(例如金缕梅、醇和草药提取物诸如洋甘菊提取物)、粘合剂/赋形剂、缓冲剂、螯合剂、成膜剂、调理剂、遮光剂、脂质、免疫调节剂和pH调节剂(例如柠檬酸、氢氧化钠和磷酸钠)。例如,通常在健康皮肤中发现的脂质(或其功能等同物)可以掺入本发明的乳液中。在某些实施方案中,脂质选自神经酰胺、胆固醇和游离脂肪酸。脂质的实例包括但不限于神经酰胺1、神经酰胺2、神经酰胺3、神经酰胺4、神经酰胺5、神经酰胺6、羟丙基双棕榈酰胺MEA和羟丙基双月桂酰胺MEA及其组合。
与真皮-表皮交界处的蛋白质结构相互作用的肽的实例包括棕榈酰二肽-5-二氨基丁酰基羟基苏氨酸和棕榈酰二肽-6二氨基羟基丁酸酯。
皮肤舒缓剂的实例包括但不限于藻类提取物、艾蒿提取物、硬脂基甘草亭酸酯、红没药醇、尿囊素、芦荟、鳄梨油、绿茶提取物、啤酒花提取物、洋甘菊提取物、胶体燕麦片、炉甘石、黄瓜提取物及其组合。
在某些实施方案中,组合物包含佛手柑或佛手柑油。佛手柑油是一种天然的爽肤水和解毒剂。
在一些实施方案中,所述组合物包含维生素。维生素的实例包括但不限于维生素A、D、E、K及其组合。还考虑了维生素类似物;例如,维生素D类似物钙泊三烯(calcipotriene)或钙泊三醇(calcipotriol)。在一些实施方案中,维生素可以作为四己基癸醇抗坏血酸酯存在。该化合物表现出抗氧化活性,抑制脂质过氧化。在某些实施方案中,使用可以减轻UV暴露的破坏作用。研究表明,它通过抑制黑色素生成(色素的产生)来刺激胶原蛋白产生以及使皮肤清洁和亮白,从而促进肤色更均匀。
在一些实施方案中,所述组合物包含防晒剂。防晒剂的实例包括但不限于对氨基苯甲酸、阿伏苯宗(avobenzone)、西诺沙酯(cinoxate)、双羟苯宗、胡莫柳酯(homosalate)、薄荷醇邻氨基苯甲酸酯、奥克立林(octocrylene)、甲氧基肉桂酸辛酯、水杨酸辛酯、氧苯酮、帕地马酯O(padimateO)、苯基苯并咪唑磺酸、磺异苯酮(sulisobenzone)、二氧化钛、三乙醇胺水杨酸盐、氧化锌、4-甲基亚苄基樟脑、亚甲基双苯并三唑基四甲基丁基苯酚、双乙基己氧基苯酚甲氧基苯基三嗪、对苯二亚甲基二樟脑磺酸、甲酚曲唑三硅氧烷(drometrizoletrisiloxane)、苯基二苯并咪唑四磺酸酯二钠、二乙氨基羟基苯甲酰基己基苯甲酸酯、辛基三嗪酮、二乙基己基丁酰氨基三嗪酮、聚硅氧烷-15及其组合。
合适的香料和着色剂可用于本发明的调配物中。适用于局部产品的香料和着色剂的实例是本领域已知的。
除噬菌体外,粉剂和喷雾剂可含有赋形剂,诸如乳糖、滑石、硅酸、氢氧化铝、硅酸钙和聚酰胺粉末,或这些物质的混合物。喷雾剂可另外含有常用的推进剂,诸如氯氟烃和挥发性未取代的烃,诸如丁烷和丙烷。
透皮贴剂具有额外的优点,即向身体提供本发明的噬菌体的受控递送。此类剂型可以通过将噬菌体溶解或分散在恰当培养基中来制备。吸收增强剂也可用于增加噬菌体进入宿主的通量。可以通过提供速率控制膜或将噬菌体分散在聚合物基质或凝胶中来控制此类通量的速率。
本发明的痤疮丙酸杆菌噬菌体可以与赋形剂和此类口服组合物或食品补充剂常用的组分一起配制,例如特别是脂肪和/或水性组分、保湿剂、增稠剂、防腐剂、组织形成剂、增味剂和/或包衣剂、抗氧化剂和防腐剂。用于口服组合物(特别是食品补充剂)的配制剂和赋形剂在本领域中是已知的,并且将不是本文详细描述的主题。
在根据本发明的用于口服施用的组合物的情况下,优选使用可摄取的支持物。根据所考虑的组合物的类型,可摄取的支持物可以具有不同的性质。片剂、凝胶胶囊剂或锭剂、混悬剂、干燥形式的口服补充剂和液体形式的口服补充剂特别适于用作食品支持物。
根据本发明的口服组合物的配制可以经由本领域技术人员已知的用于生产可饮用溶液、糖衣片剂、凝胶胶囊、凝胶、乳剂、待吞咽或咀嚼的片剂、糯米胶囊(特别是软或硬糯米胶囊)、待溶解的粒剂、糖浆剂、固体或液体食品以及允许控释的水凝胶的任何常见方法进行。
具体而言,根据本发明的痤疮丙酸杆菌噬菌体可以掺入任何形式的食品补充剂或强化营养食品,例如食物棒,或压实或松散粉剂中。粉剂可以用水、苏打、乳制品或大豆衍生物稀释,或者可以掺入食物棒中。
在一些实施方案中,口服施用的根据本发明的组合物可以配制成糖衣片剂、凝胶胶囊、凝胶、乳剂、片剂、糯米胶囊、水凝胶、食物棒、压实或松散粉剂、液体混悬剂或溶液、糖果、发酵乳、发酵奶酪、口香糖、牙膏或喷雾溶液的形式。
有效量的噬菌体可以每天以单剂量施用或在一天内以分次剂量施用,例如每天两到三次。举例而言,根据本发明的噬菌体的施用可以按例如每天3次或更多次的速率进行,通常在至少一周、2周、3周、4周,或甚至4至15周内长期进行,任选地包括一个或多个停止时段或在停止一段时间后重复。
如本领域技术人员将理解的,可以每天向受试者施用本发明的组合物,该组合物在施用于受试者后没有不利影响。
本文描述了本发明的优选实施方案。当然,在阅读前面的描述之后,那些优选实施方案的改变、变化、修改和等效方案的替换对于本领域普通技术人员来说将变得显而易见。本发明人期望本领域技术人员适当地使用此类改变、变化、修改和等效方案的替换,并且本发明人打算以除本文具体描述以外的其它方式来实践本发明。本领域技术人员将容易认识到可以变化、改变或修改各种非关键参数以产生基本相似的结果。因此,本发明包括适用法律所容许的所附权利要求书中叙述的主题的所有修改和等效方案。而且,在其所有可能的改变中,上述要素的任何组合均由本发明涵盖,除非本文另外指出或与上下文明显矛盾。
虽然本发明的每个要素在本文中被描述为包含多个实施方案,但是应当理解,除非另有说明,否则本发明的给定要素的每个实施方案都能与本发明的其它要素的每个实施方案一起使用并且每种此类使用旨在形成本发明的不同实施方案。
本文引用的参考专利、专利申请和科学文献均据此通过引用整体并入本文,如同特别且单独地指出将每个单独的公开案、专利或专利申请通过引用并入一样。本文引用的任何参考文献与本说明书的具体教导之间的任何冲突都应以有利于后者的方式解决。同样,本领域理解的单词或短语的定义与本说明书中具体教导的单词或短语的定义之间的任何冲突都应以有利于后者的方式解决。
正如从以上公开内容可以认识到的那样,本发明具有各种各样的应用。通过以下实施例进一步说明本发明,这些实施例仅为说明性,并非旨在以任何方式限制本发明的定义和范围。
V.实施例
以下实施例旨在说明本文所述方法和组合物的具体实施方案,并不应解释为以任何方式限制本发明的范围。
实施例1
背景和初步数据
痤疮丙酸杆菌和痤疮丙酸杆菌噬菌体的分离。最初,噬菌体用于对痤疮丙酸杆菌菌株分型,并且发现一些噬菌体针对痤疮丙酸杆菌临床亚型表现出广泛的宿主范围(30-32)。然而,尽管可以相对容易地从人体皮肤中分离出痤疮丙酸杆菌噬菌体,但仅报道了三种痤疮丙酸杆菌噬菌体的完整基因组序列(33,34),并且对它们的遗传多样性或它们与其细菌宿主的关系的分子基础知之甚少(33,34)。从健康个体和痤疮患者中对11种新型痤疮丙酸杆菌噬菌体进行测序,并进行详细的基因组对比分析以及这些噬菌体的表型表征(1)。惊人地发现在形态学、基因含量、核苷酸序列和宿主范围方面缺乏多样性。
所有噬菌体都具有相同的长尾病毒(siphoviral)形态,具有直径约为50nm的等长头部和长柔性尾部。这些非常类似于先前报道的痤疮丙酸杆菌噬菌体(32-36),并且缺乏在其它噬菌体群体中观察到的形式多样性。例如,分枝杆菌噬菌体-与痤疮丙酸杆菌噬菌体遗传相关-同时具有长尾病毒(长非收缩性尾部)和肌病毒形态(收缩性尾部)-包括具有扁长头部的那些(37,38)-并且其它宿主的噬菌体(例如大肠埃希氏菌(E.coli)、葡萄球菌属(Staphylococcus)和假单胞菌属(Pseudomonas)噬菌体)包括短尾病毒(podoviral)形态(即具有短粗尾部)(39,40)。
痤疮丙酸杆菌噬菌体的基因组表征。所有11种噬菌体的基因组大小相似(29.5kbp),并且结构与先前报道的3种痤疮丙酸杆菌噬菌体相似(33,34),并且基因组与基因组之间的GC%几乎没有变化(尽管它不同于痤疮丙酸杆菌宿主)。这与其它噬菌体相当大的GC%变化形成对比。在全部14个基因组中存在高水平的核苷酸序列相似性,并且这种多样性的缺乏与噬菌体群体的普遍多样性相背离。痤疮丙酸杆菌噬菌体基因组图谱的比对揭示了噬菌体基因组惊人的相似性。最后,有限的痤疮丙酸杆菌噬菌体多样性通过基因含量网络图得以说明。(1)
痤疮丙酸杆菌噬菌体基因组的构成。痤疮丙酸杆菌噬菌体基因组相对较小(30kbp),并且有DNA包装和病毒粒子结构及组装基因(1-19)构成,其占据向右转录的操纵子中基因组的左半部分(坐标1–~15kbp),具有几个基因间空位(图1)。这些基因在核苷酸水平上是高度保守的,除了最后一个假定小尾蛋白基因(P100D基因19及其亲缘基因)明显例外(34)。这些基因的3'半部分内的变异最大,并且蛋白质产物在相应的C末端部分中变化明显。其高甘氨酸含量(~20%)和可变数量的胶原蛋白样GXXG重复序列(从17到42)的存在支持其可能作为尾丝的作用,并且该变异可能有助于宿主识别和宿主范围测定。在尾部基因右侧的编码内溶素(gp20)和假定穴蛋白(gp21)的裂解盒促进肽聚糖水解和细胞裂解(41)。
除了最右端的1-2个基因外,其它基因向左转录,间隔很近,并且可能共转录(图1)。只有少数具有预测功能,并且这些参与DNA代谢和调节,包括分别编码DNA引发酶、DnaB样解旋酶和RecB样外切核酸酶的P100D基因30/31、33和36(及其亲缘基因)。P100D基因23及其亲缘基因编码具有强预测螺旋-转角-螺旋DNA结合基序的潜在阻遏物。大约三分之一的基因具有分枝杆菌噬菌体同源物(1)。
痤疮丙酸杆菌噬菌体宿主偏好和CRISPR介导的抗性。痤疮丙酸杆菌噬菌体针对一组27个痤疮丙酸杆菌菌株具有广泛但不通用的宿主范围。大多数噬菌体感染所有宿主菌株-尽管涂铺效率可变。然而,两个菌株-B66.8和B101.9-区别在于它们分别对9种和10种噬菌体具有高度抗性;与菌株6919相比,涂铺效率降低至少100,000倍。抗性可能由多种机制引起,包括受体变异、限制-修饰、顿挫性感染、溶原性免疫或CRISPR所赋予的先天免疫(42)。然而,已经描述了痤疮丙酸杆菌基因组中I-E型亚家族的CRISPR(43),并且六个痤疮丙酸杆菌分离株具有CRISPR相关(Cas)基因,表明它们具有相似的CRISPR基因座。这些中的两个(B66.8和B101.9)具有9-10个间隔序列-其中一些间隔序列与噬菌体原间隔序列紧密匹配-并且具噬菌体抗性(1)。另外四个具有很少无噬菌体匹配的间隔序列,并且对噬菌体敏感。基因组对比分析支持这样的假设:CRISPR间隔序列是造成含有匹配原间隔序列的噬菌体的抗性的原因(1)。预计将获得具有新间隔序列的痤疮丙酸杆菌,但尚未得到证实。
CRISPR逃逸突变体。在非许可性寄主上涂铺高滴度噬菌体裂解物可以显示宿主范围扩大的突变体。例如,检测到能够感染菌株B101.9的噬菌体P9.1噬菌斑,频率为~10-6。繁殖了四个单独的噬菌斑,显示以相同效率重新感染两个宿主,并将突变作图到原间隔序列(图2)。已经用八种其它宿主-噬菌体组合观察到突变体,但尚未进行基因组学表征。
痤疮丙酸杆菌噬菌体裂解效率。从ATCC获得噬菌体ATCC29399B原液。涂铺后在细菌宿主ATCC6919上观察到两个噬菌斑形态,一个是透明的并且一个是混浊的(图3)。这些噬菌体称为ATCC_C(透明)和ATCC_T(混浊)。ATCC_C不是ATCC_T的简单裂解(阻遏因子缺陷型)变体,因为基因组分析显示1,420个核苷酸差异全部作图在坐标22和13,920之间,在病毒粒子结构和组装基因内(在所有基因1-17中,图中1)。表型可能由结构基因表达的破坏而产生,但不是因阻遏因子丢失而产生。由于治疗需要有效的杀伤,因此这些观察结果对于一般方法很重要。尽管噬菌体基因组多样性惊人的有限,但在这里我们利用有限的差异来确定如目标3中提出的调节裂解功效的机制。我们注意到ATCC_C幸存者仍然易受感染,并且可能由染色体基因座的重组依赖性局部扩增而引起。
实验计划
为优化痤疮丙酸杆菌噬菌体以用作痤疮治疗方式,可以进行简单实验。
1.对能够规避CRISPR和其它抗性机制的“超级噬菌体”的遗传选择。成功的痤疮噬菌体治疗将受益于感染和杀伤所有或几乎所有临床范围的与疾病相关的痤疮丙酸杆菌菌株的病毒。在实践中,需要大范围的噬菌体来规避预期的抗性发展。超越现有的发现痤疮丙酸杆菌噬菌体具有有限的遗传多样性并且具有广泛的宿主范围,可以鉴定和选择将规避宿主抗性机制的超级噬菌体。例如,靶向噬菌体中特定序列、赋予原核先天免疫系统以及尾丝-受体相互作用的CRISPR元件可能是优化的重要区域。基于“超级噬菌体”必须对CRISPR抗性免疫的假设,正向遗传策略可用于分离逃避CRISPR防御或其它宿主防御机制的噬菌体。
1.1.通过连续选择痤疮丙酸杆菌临床分离株来分离克服抗性的逃逸突变体。两个痤疮丙酸杆菌分离株,B66.8和B101.9,显示出高水平的噬菌体抗性,这可能是由于CRISPR介导的干扰导致的(1)。以高滴度(>109个噬菌斑形成单位[pfus])的它们对其有抗性的每种噬菌体(噬菌体P1、P8、P14、P100A、P100D、P100.1、P101A、P104A和P105)激发这些分离株可以导致鉴定出其它突变体。对于ATTC_C,B101.9具有抗性并且B66.8具有部分抗性。可将高滴度裂解物连续涂铺在每个细菌分离株菌苔上,并纯化各个噬菌斑并制备高滴度原液。例如,可以使用12种独立的裂解物(从单个噬菌斑生长而成),从每种裂解物中回收1-2个突变体,并与当前的突变体一起分析。通过迭代分离和测试突变体,可以鉴定引起宿主偏好测定的广泛突变。
1.2.使用已知核糖体型的痤疮丙酸杆菌临床分离株建立这些突变体的宿主范围。可以通过测量涂铺从毛囊皮脂腺单位分离并根据16SrDNA核糖体型分类的不同痤疮丙酸杆菌株的效率来测定每种突变体的宿主偏好。描述了十种主要的核糖体型,其中两种RT4和RT5与痤疮相关而RT6与正常皮肤相关(29)。值得注意的是,在存在于痤疮和健康皮肤中的RT2中和主要存在于健康皮肤中的RT6中发现了CRISPR元件,而在源自痤疮患者的核糖体型中未发现。对疾病特异性核糖体型和特定核糖体型中CRISPR的存在的鉴定是初步的。尽管如此,90个痤疮丙酸杆菌菌株的集合含有前六种核糖体型中的每一种的至少3个菌株,并且总共有12个含有CRISPR的菌株。宿主范围分析可以使用来自RT2和RT6的所有12个CRISPR菌株和其它4种核糖体型中的每一种的3个菌株进行,总共24个菌株。在该宿主范围分析期间,可以观察到出现在其它抗性菌株上的其它逃逸突变体,并且如果是这样,可以如1中那样对其进行回收和表征。
1.3.通过野生型相对于突变体噬菌体的对比基因组学探索抗性机制。
通过对来自每个宿主-噬菌体对的两个分离株的整个基因组进行测序,可以确定突变是否位于原间隔序列内。如果是这样,所有分离株的原间隔序列区的PCR扩增和测序可以鉴定广泛范围的突变事件。如果在原间隔序列外存在突变,可以将测序扩展到更多的全噬菌体基因组。
回收其中原间隔序列改变的并且规避CRISPR介导的干扰的噬菌体将鉴定导致抗性的关键CRISPR-原间隔序列匹配。工程化噬菌体基因组以询问原间隔序列突变的特定作用可以帮助将各个突变的影响分隔开。此外,与疾病相关的缺乏CRISPR或特定间隔序列的痤疮丙酸杆菌菌株核糖体型可能由于获得CRISPR(或间隔序列)或其它机制而变成抗噬菌体的。正向遗传方法将能够广泛了解噬菌体抗性的可能遗传基础。
将有益突变组合到单个(或少量)‘超级噬菌体’中将会容许这些改良菌株被开发为治疗剂,或与用于靶向递送的现有药物组合。
2.通过工程化噬菌体基因组来构建“超级噬菌体”。使用正向遗传策略鉴定CRISPR逃逸突变体将允许鉴定对CRISPR介导的免疫具有更高抗性的噬菌体。然而,不可能产生具有所有所需宿主范围特性的单一分离株,并且各个突变的作用将不明确。对于有效的噬菌体疗法,将必须杀伤所有痤疮丙酸杆菌菌株,降低痤疮丙酸杆菌载量,并预测病原菌株对CRISPR的获得。掺入许多有利突变的“超级噬菌体”可能对实现这些目标非常有用。
2.1.开发痤疮丙酸杆菌系统用于重组工程化(使用分枝杆菌噬菌体编码的重组酶)。调整Hatfull实验室(44)为分枝杆菌噬菌体基因组开发的电穿孔DNA的噬菌体重组工程化(BRED)方法用于痤疮丙酸杆菌及其噬菌体(痤疮丙酸杆菌重组工程化系统不可用)将有助于产生所需的噬菌体基因组。可以在痤疮丙酸杆菌中对分枝杆菌重组工程化质粒(45-48)进行评价,或者可以生成含有重组工程化功能和诱导型表达系统加上痤疮丙酸杆菌质粒复制特性的新型质粒(49)。可以将这些质粒引入痤疮丙酸杆菌(49),并且可以使用引入抗药性突变的ssDNA底物测定重组(45)。这是有效的并且能够实现快速优化。这些技术可以适用于使用BRED策略进行噬菌体DNA工程化(44)。
2.2.使用重组工程化系统测试各个噬菌体突变在宿主抗性中的作用。重组工程化将用于构建具有表1所标识的单个突变的限定噬菌体突变体。可以使用如前所述的噬菌体基因组DNA进行工程化(44),并且可以引入单个突变以产生同基因噬菌体菌株。可以通过PCR鉴定突变体,纯化并制备原液。然后将会评价这些突变体的宿主偏好。
2.3.使用重组工程化系统构建具有所需特征以及其它潜在的改进的超级噬菌体。在第二轮诱变中,可以将多个突变组合到单个噬菌体骨架基因组中以实现最广泛的可能宿主范围。可以采用突变体构建和宿主范围测试的迭代过程。特定突变可能产生可预测的宿主范围表型,但在其它情况下可能不会,尤其是在除了CRISPR之外的机制赋予抗性的情况下。然而,这些也可能导致噬菌体突变体/宿主组合产生可以分离和表征的逃逸突变体。正向和反向遗传方法的这种整合为整体战略提供了强大而有吸引力的方面。
工程化噬菌体基因组的能力开辟了广泛的改进,这可以增强噬菌体的用途。例如,已经描述了抗CRISPR噬菌体基因(50),并且可以将这些(或相关形式)工程化到痤疮丙酸杆菌噬菌体基因组中,其目的在于增加广泛的CRISPR避免性,这是可以克服相对短暂的突变CRISPR避免性的策略。还可以工程化限制复制轮数并因此是自我限制的突变。
鉴于丙酸杆菌和分枝杆菌之间的系统发育相关性,分枝杆菌重组工程化系统可以适于在痤疮丙酸杆菌中起作用,例如优化蛋白质表达和电穿孔。或者,可以使用耻垢分枝杆菌(M.smegmatis)作为替代宿主,使痤疮丙酸杆菌噬菌体DNA电穿孔进入精于重组工程化的耻垢分枝杆菌中并在感染中心测定中涂铺在痤疮丙酸杆菌菌苔上。耻垢分枝杆菌作为替代用于痤疮丙酸杆菌噬菌体遗传学的用途很有吸引力,这是因为它的简单性,充分利用分枝杆菌遗传工具箱的潜力,并且先前已经证实类似替代宿主的用途(28)。依赖于宿主介导的交换和广泛筛选以鉴定突变体的其它突变体构建策略也可用,但是比重组工程化效率低。
采用痤疮丙酸杆菌上的重组工程化系统能够构建限定的噬菌体突变体和具有多个所需突变的噬菌体。
3.分离具有对痤疮丙酸杆菌分离株的最佳杀伤效力的“超级噬菌体”。从痤疮和健康皮肤的毛囊皮脂腺单位中分离的噬菌体在其裂解痤疮丙酸杆菌的效率方面是可变的。用于治疗痤疮的改良“超级噬菌体”将受益于广泛的宿主范围并且具有高效力。作图赋予噬菌体有效杀伤痤疮丙酸杆菌临床分离株的能力的定子将有助于阐明各种影响的相互作用。
3.1.对ATCC_C中增强的杀伤表型的遗传定子进行作图。噬菌体ATCC_C是痤疮丙酸杆菌的有效杀手而ATCC_T不是。通过对遗传定子进行作图,可以了解哪些突变添加到超级噬菌体中会优化效力。两者之间存在>1,420个碱基差异,但都在左臂结构基因内。可以容易地实现对负责表型的差异的作图。可以使用适合的BRED重组工程化(如以上所讨论的)将独特限制性位点引入两个噬菌体中,间隔约5kbp。然后可以在体外消化和重新连接基因组,并确定重组体的效力表型。一旦突变被作图到5kbp间隔,然后可以进行简单的噬菌体杂交,回收重组体,对间隔进行测序,并将突变与表型相关联。将已鉴定的突变重新组合成清晰的遗传背景并确认有助于杀死效力的突变和基因完成了该过程。
3.2.构建具有CRISPR抗性且具有很强效力的治疗性噬菌体。重组工程化可用于构建携带最大宿主范围和效力所需的所有突变的超级噬菌体。某些突变之间可能存在遗传冲突,并且可能有必要构建几种不同的特定组合。如果从其它表型比较中出现另外的效力突变,则可以将这些突变添加到超级噬菌体中。可以用一系列跨越不同核糖体型的痤疮丙酸杆菌临床分离株测试所有噬菌体的效力。
使用BRED策略可以实现ATCC突变的作图。然而,可以替代地或另外应用仅依赖于噬菌体杂交的替代策略,或来自重组质粒的作图。例如,构建携带噬菌体基因组区段的重组质粒,使噬菌体在这些菌株上繁殖,以及鉴定重组体也可以实现预期目标。
对有助于有效杀伤的突变进行作图增强了噬菌体的治疗潜力,并且当与广泛的宿主范围组合时将有益于超级噬菌体的有效性。
实施例2-痤疮丙酸杆菌噬菌体CRISPR逃逸突变体
规律成簇的间隔短回文重复序列(称为CRISPR)是细菌编码的染色体元件,其介导噬菌体抗性。CRISPR以序列特异性方式起作用;即,噬菌体抗性取决于CRISPR基因座中称为‘间隔序列’的区段与噬菌体基因组中称为‘原间隔序列’的相应区域之间的序列同源性。
这些中的六个痤疮丙酸杆菌临床分离株含有CRISPR基因座,并且这些中有两个(B66.8和B101.9)具有多个与噬菌体基因组中的区段匹配的间隔序列,因此预测会赋予抗性。因此,这些分离株确实显示出广泛的噬菌体抗性,这与间隔序列匹配相关,强烈暗示这是由于CRISPR介导的干扰所引起(1)。(Marinelli等人,2012,参见图9)。
基于这些观察,设法分离克服这种抗性的CRISPR逃逸突变体。以高滴度(>109个噬菌斑形成单位[pfus])的它们对其有抗性的每种噬菌体(噬菌体P1、P8、P14、P100A、P100D、P100.1、P101A、P104A和P105)激发分离株。尽管大多数噬菌体不能有效感染这些抗性分离株,但在一些情况下,噬菌斑在这些条件下以低频率回收。回收并纯化获得的噬菌斑并确认其表型(例如有效感染含有CRISPR的抗性分离株的能力)。参见图4。
对假定突变体的原间隔序列区进行测序以确定这些是否在CRISPR逃逸噬菌体中突变。如预测的那样,发现CRISPR逃逸突变体在其原间隔序列区中含有点突变(而确认野生型噬菌体在原间隔序列区内不含任何点突变)。另外,在一个含CRISPR的痤疮丙酸杆菌菌株上分离的突变体能够有效感染其它CRISPR抗性分离株;目前,正在测试其它含CRISPR的分离株(来自BEI)是否是这样以及这些噬菌体是否可能进一步进化以增强针对痤疮丙酸杆菌的毒力。参见图5和6。CRISPR逃逸突变体基因组中所有点突变的位置和特性可以在下表中找到。
表1:
1S=同义突变,NS=非同义突变
2(PAM)表示突变出现在所示PS相关的PAM中
下面表2显示了当对逃逸突变体基因组进行测序以鉴定突变时涂铺的效率。
此外,逃逸突变在PS的5'末端富集。见下文:
·数字表示回收突变体的次数
·突出显示的残基表示CRISPR逃逸突变体噬菌体中突变的那些残基
·带箭头的残基表示出现在野生型噬菌体中但未使PS失活的残基(例如,当该残基突变时,需要至少一个附加突变才能逃逸)
·带有星号的残基表示在某些情况下不会使PS失活,但是可以与其它突变组合介导逃避的残基
·带下划线的残基也是似乎会使野生型P1.1中的B101.9/B66.8PS-4失活的残基;然而,它是B66.8PS-1中错配的相同残基并且逃逸突变体似乎需要至少一个附加突变才能逃逸
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SEQ ID NO:7
丙酸杆菌噬菌体P1.1基因组
GenBank登录号JX262223.1
SEQ ID NO:8
丙酸杆菌噬菌体P1.1基因3蛋白产物-门户蛋白
由SEQ ID NO:7的残基1886-3211编码
GenBank登录号AFT97827.1
SEQ ID NO:9
丙酸杆菌噬菌体P1.1基因7蛋白产物-假设蛋白
由SEQ ID NO:7的残基5618-6097编码
GenBank登录号AFT97831.1
SEQ ID NO:10
丙酸杆菌噬菌体P1.1基因9蛋白产物-假设蛋白
由SEQ ID NO:7的残基6453-6743编码
GenBank登录号AFT97833.1
SEQ ID NO:11
丙酸杆菌噬菌体P1.1基因16蛋白产物-假设蛋白
由SEQ ID NO:7的残基12239-13399编码
GenBank登录号AFT97840.1
SEQ ID NO:12
丙酸杆菌噬菌体P9.1基因组
GenBank登录号JX262215.1
SEQ ID NO:13
丙酸杆菌噬菌体P9.1基因3蛋白产物-门户蛋白
由SEQ ID NO:12的残基1881-3206编码
GenBank登录号AFT97459.1
SEQ ID NO:14
丙酸杆菌噬菌体P9.1基因7蛋白产物-假设蛋白
由SEQ ID NO:12的残基5610-6089编码
GenBank登录号AFT97463.1
SEQ ID NO:15
丙酸杆菌噬菌体P9.1基因9蛋白产物-假设蛋白
由SEQ ID NO:12的残基6445-6735编码
GenBank登录号AFT97465.1
SEQ ID NO:16
丙酸杆菌噬菌体P9.1基因16蛋白产物-假设蛋白
由SEQ ID NO:12的残基12238-13398编码
GenBank登录号AFT97472.1
Claims (43)
1.一种痤疮丙酸杆菌(P.Acnes)噬菌体突变体,其能够感染噬菌体抗性痤疮丙酸杆菌。
2.根据权利要求1所述的噬菌体突变体,其中所述噬菌体突变体是规律成簇的间隔短回文重复序列(CRISPR)逃逸突变体。
3.根据权利要求1或2所述的噬菌体突变体,其在选自1、3和4的原间隔序列中包含一种或多种突变。
4.根据前述权利要求中任一项所述的噬菌体突变体,其包含选自以下的一种或多种突变:T6502G、C6514A、G2762T、T2757C、G5919T、C5917A和A5892C。
5.根据前述权利要求中任一项所述的噬菌体突变体,其中所述噬菌体突变体选自P9.1-2A、P9.1-2B、P9.1-3和P9.1-4。
6.根据前述权利要求中任一项所述的噬菌体突变体,其中:
所述噬菌体包含与SEQ ID NO:1或其反向互补序列具有至少约95%序列同源性的核苷酸序列;并且
所述核苷酸序列包含对选自SEQ ID NO:1的A2、A3、T5、C6、T7、T8、C9、G11、G12、G13、G14、C17、G20、G21和G22的一个或多个核苷酸的突变。
7.根据权利要求6所述的噬菌体突变体,其中所述核苷酸序列包含选自A2T、A2C、A3C、T5G、G11T、G14T、C17A、G20T、G21C、C22G和C22T的对SEQ ID NO:1的一种或多种突变。
8.根据权利要求6或7所述的噬菌体,其中所述噬菌体的基因9包含所述核苷酸序列。
9.根据前述权利要求中任一项所述的噬菌体突变体,其中:
所述噬菌体包含与SEQ ID NO:2或其反向互补序列具有至少约95%序列同源性的核苷酸序列;并且
所述核苷酸序列包含对选自SEQ ID NO:2的A2、A3、T5、C6、T7、T8、C9、G11、G12、G13、G14、C17、T20、C21和T22的一个或多个核苷酸的突变。
10.根据权利要求9所述的噬菌体突变体,其中所述核苷酸序列包含选自A2T、A2C、A3C、T5G、G11T、G14T、C17A、T20G、C21G、T22G和T22C的对SEQ ID NO:2的一种或多种突变。
11.根据权利要求9或10所述的噬菌体,其中所述噬菌体的基因9包含所述核苷酸序列。
12.根据前述权利要求中任一项所述的噬菌体突变体,其中:
所述噬菌体包含与SEQ ID NO:3或其反向互补序列具有至少约95%序列同源性的核苷酸序列;并且
所述核苷酸序列包含对选自SEQ ID NO:3的A2、A3、A5、T6、T7、G8、A9、T11、T12、G13、G14、T20、G23、T25、T30和G31的一个或多个核苷酸的突变。
13.根据权利要求12所述的噬菌体突变体,其中所述核苷酸序列包含选自T7C、T20G、G23A、T25G、T30G和G31T的对SEQ ID NO:3的一种或多种突变。
14.根据权利要求12或13所述的噬菌体,其中所述噬菌体的基因16包含所述核苷酸序列。
15.根据前述权利要求中任一项所述的噬菌体突变体,其中:
所述噬菌体包含与SEQ ID NO:4或其反向互补序列具有至少约95%序列同源性的核苷酸序列;并且
所述核苷酸序列包含对选自SEQ ID NO:4的A2、A3、T5、G6、C7、G8、C9、A11、A12、C13、A14、A15、A16和G18的一个或多个核苷酸的突变。
16.根据权利要求15所述的噬菌体突变体,其中所述核苷酸序列包含选自A3T、A3C、A3G、C7A、C9A、A12G、C13A、A15G、A16C、A16T和G18T的对SEQ ID NO:4的一种或多种突变。
17.根据权利要求15或16所述的噬菌体,其中所述噬菌体的基因3包含所述核苷酸序列。
18.根据前述权利要求中任一项所述的噬菌体突变体,其中:
所述噬菌体包含与SEQ ID NO:5或其反向互补序列具有至少约95%序列同源性的核苷酸序列;并且
所述核苷酸序列包含对选自SEQ ID NO:5的A2、A3、T5、G6、C7、G8、C9、A11、A12、C13、A14、G15、T16和T18的一个或多个核苷酸的突变。
19.根据权利要求18所述的噬菌体突变体,其中所述核苷酸序列包含选自A3T、A3C、A3G、C7A、C9A、A12G、C13A、G15A、T16C、T16A和T18G的对SEQ ID NO:5的一种或多种突变。
20.根据权利要求18或19所述的噬菌体,其中所述噬菌体的基因3包含所述核苷酸序列。
21.根据前述权利要求中任一项所述的噬菌体突变体,其中:
所述噬菌体包含与SEQ ID NO:6或其反向互补序列具有至少约95%序列同源性的核苷酸序列;并且
所述核苷酸序列包含对选自SEQ ID NO:6的A2、A3、G5、C6、A7、G8、C9、A11、T12、C13、T14、A31、T33和G35的一个或多个核苷酸的突变。
22.根据权利要求21所述的噬菌体突变体,其中所述核苷酸序列包含选自C6A、A7G、G8T、A31G、T33G和G35A的对SEQ ID NO:6的一种或多种突变。
23.根据权利要求21或22所述的噬菌体,其中所述噬菌体的基因7包含所述核苷酸序列。
24.根据前述权利要求中任一项所述的噬菌体,其中所述噬菌体的基因组与SEQ IDNO:7具有至少约95%、96%、97%、98%或99%的序列同源性,并且所述噬菌体包含选自G2761T、T2762C、G2767T、T2771C、T2771G、C6477A、A6507C、A6508C、T13160G、T13170G、G13171T、C13734A、T20501G、C23365A、G27713T、T28115G和G28199T的一种或多种突变。
25.根据前述权利要求中任一项所述的噬菌体,其中所述噬菌体的基因组与SEQ IDNO:12具有至少约95%、96%、97%、98%或99%的序列同源性,并且所述噬菌体包含选自T2757C、G2760T、G2762T、T2766C、G3704T、C5890A、C5890T、A5892C、C5917A、G5919T、A6499C、T6502G、G6508T、G6511T、C6514A、A12404C、C16536A、G17863T和G26907A的一种或多种突变。
26.一种药物组合物,其包含一种或多种根据前述权利要求中任一项所述的噬菌体突变体。
27.根据权利要求26所述的药物组合物,其还包含一种或多种抗微生物剂。
28.根据权利要求27所述的药物组合物,其中所述抗微生物剂是抗痤疮剂。
29.根据权利要求28所述的药物组合物,其中所述抗痤疮剂选自类视黄醇、过氧化苯甲酰和抗生素。
30.根据前述权利要求中任一项所述的药物组合物,其中所述药物组合物经配制用于局部使用。
31.一种用于治疗有需要的受试者的痤疮的方法,其包括向受试者施用治疗有效量的组合物,所述组合物包含一种或多种能够感染噬菌体抗性痤疮丙酸杆菌的痤疮丙酸杆菌(P.Acnes)噬菌体突变体。
32.根据权利要求31所述的方法,其中所述痤疮与噬菌体抗性痤疮丙酸杆菌相关。
33.根据权利要求31或32所述的方法,其中所述噬菌体突变体是规律成簇的间隔短回文重复序列(CRISPR)逃逸突变体。
34.根据前述权利要求中任一项所述的方法,其中所述噬菌体突变体在选自1、3和4的原间隔序列中包含一种或多种突变。
35.根据前述权利要求中任一项所述的方法,其中所述噬菌体突变体包含选自以下的一种或多种突变:T6502G、C6514A、G2762T、T2757C、G5919T、C5917A和A5892C。
36.根据前述权利要求中任一项所述的方法,其中所述噬菌体突变体选自P9.1-2A、P9.1-2B、P9.1-3和P9.1-4。
37.根据前述权利要求中任一项所述的方法,其中所述药物组合物包含根据前述权利要求中任一项所述的一种或多种噬菌体突变体。
38.根据前述权利要求中任一项所述的方法,其中所述药物组合物包含一种或多种抗微生物剂。
39.根据权利要求38所述的方法,其中所述抗微生物剂是抗痤疮剂。
40.根据权利要求39所述的方法,其中所述抗痤疮剂选自类视黄醇、过氧化苯甲酰和抗生素。
41.根据前述权利要求中任一项所述的药物组合物,其用于治疗痤疮。
42.根据前述权利要求中任一项所述的药物组合物用于治疗痤疮的用途。
43.根据前述权利要求中任一项所述的药物组合物用于制造治疗痤疮的药物的用途。
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CA3021793A1 (en) | 2016-04-21 | 2017-10-26 | Naked Biome, Inc. | Compositions and methods for treatment of skin disorders |
US20210338569A1 (en) | 2017-04-21 | 2021-11-04 | Phi Therapeutics, Inc. | Compositions comprising propionibacterium acnes bacteriophages for treating acne |
JP2021505667A (ja) * | 2017-12-05 | 2021-02-18 | バイオミックス リミテッド | ざ瘡およびバイオフィルムに対するバクテリオファージ処置 |
IL302448A (en) * | 2020-11-04 | 2023-06-01 | Eligo Bioscience | Phage-derived particles for in situ delivery of DNA cargo into the C. acnes population |
KR102510118B1 (ko) * | 2022-06-17 | 2023-03-15 | 주식회사 마이크로진 | 큐티박테리움 애크니스에 대한 사멸능을 갖는 박테리오파지 cap-1 |
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