CN116898840A - 抗微生物组合物、医药组合物及其用途 - Google Patents
抗微生物组合物、医药组合物及其用途 Download PDFInfo
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- CN116898840A CN116898840A CN202310234927.0A CN202310234927A CN116898840A CN 116898840 A CN116898840 A CN 116898840A CN 202310234927 A CN202310234927 A CN 202310234927A CN 116898840 A CN116898840 A CN 116898840A
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- fatty acid
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- staphylococcus aureus
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Abstract
本发明公开了一种抗微生物组合物以及相关方法。藉由其组合物中酰胺化合物及脂肪酸的协同作用，不但能以更少用量的酰胺化合物达到针对抗药性细菌的抗菌效果，更能够有效并快速地根除微生物的持久性细胞及生物膜。
Description
【技术领域】
本发明是关于一种抗微生物组合物及相关方法，特别是关于一种抗微生物组合物、包含其之医药组合物以及其用途；然而本发明并不以此为限。
【背景技术】
人类疾病的病原体五花八门，且对于全球公共卫生有着巨大的影响；其中最为常见的便为具致病性的细菌以及真菌。尤其，金黄色葡萄球菌(Staphylococcus aureus)是现阶段已开发国家中最为常见的传染性病原体之一；其能引发多种疾病，从皮肤感染到致命的肺炎及败血症皆有所见。再者，金黄色葡萄球菌能够形成耐抗生素的持久性细胞及生物膜，进而导致慢性和复发性感染；又，金黄色葡萄球菌已对多数抗生素发展出抗药性，更进一步使其治疗的难度及复杂度更为提升。
有鉴于此，先前技术中不乏各种针对多重抗药性金黄色葡萄球菌的抗菌手段。举例而言，本案发明人先前发现，原先作为抗癌药物的酪氨酸激酶抑制剂-索拉非尼(Sorafenib)之衍生物藉由去极化和穿透细菌膜，对于多种菌株皆具有效的抗菌活性(中国台湾地区发明专利证书号：TW I675817B)。另亦有研究显示索拉非尼之相似物PK150在亚微摩尔浓度下能治疗多种病原体菌株，并且具有口服生物利用性及体内药效(Le,P etal.Nat.Chem.12,145–158(2020))。
【发明内容】
基于先前技术的内容，本案发明人在开发过程中进一步发现，特定的酰胺化合物与特定脂肪酸的共同使用下，得以产生协同的杀菌效果；搭配脂肪酸不但能令所述酰胺化合物在更少的用量下达到针对抗药性菌株的治疗效果，更能够有效并快速地消灭微生物的持久性细胞及生物膜。
具体而言，本发明一方面提供一种抗微生物组合物，其包括：酰胺化合物；以及脂肪酸；其中，该脂肪酸是一具有16至22个碳原子的顺式不饱和脂肪酸。
根据本发明的一实施例，该酰胺化合物是一具有化学结构(I-1)或(I-2)的化合物：
其中R1及R2分别为 且R1及R2非同时为/>
R3为氢、甲苯、R4为氢或氟。
根据本发明的一实施例，R1为 而R2为
根据本发明的一实施例，该酰胺化合物是一具有化学结构(II)之化合物：
其中R1为
R2为
根据本发明的一实施例，该酰胺化合物是具有化学结构(III)至(VII)中任一者的化合物：
根据本发明的一实施例，该脂肪酸是一具有16至22个碳原子的顺式单不饱和脂肪酸或顺式多不饱和脂肪酸。
根据本发明的一实施例，该脂肪酸是一棕榈油酸、油酸、亚油酸、α-亚油酸、花生四烯酸、二十碳五烯酸或二十二碳六烯酸。
根据本发明的一实施例，该脂肪酸的含量大于该酰胺化合物的含量。
本发明另一方面提供一种医药组合物，其包含上述抗微生物组合物以及至少一医药上可接受的载体。
本发明又另一方面提供上述抗微生物组合物的用途，其用于制备用于抑制微生物细胞以及微生物生物膜生长的药剂。
根据本发明的一实施例，该微生物细胞为人类致病菌的细胞。
根据本发明的一实施例，该人类致病菌是选自由金黄色葡萄球菌、溶血葡萄球菌(S.haemolyticus)、人葡萄球菌(S.hominis)、中间葡萄球菌(S.intermedius)、腐生葡萄球菌(S.saprophyticus)、路邓葡萄球菌(S.lugdunesis)、猪红斑丹毒丝菌(Erysipelothrixrhusiopathiae)、粪肠球菌(Enterococcus faecalis)、屎肠球菌(Enterococcusfaecium)、万古霉素抗性屎肠球菌(VR-E.faecium)、蜡样芽孢杆菌(Bacillus cereus)、枯草芽孢杆菌(Bacillus subtilis)、白喉杆菌(Corynebacterium diphtheriae)、李斯特单胞菌(Listeria monocytogenes)、酿脓链球菌(Streptococcus pyogenes)、困难梭状芽孢杆菌(Clostridium difficile)、大肠杆菌(Escherichia coli)、鼠伤寒沙门杆菌(Salmonelia Typhimurium)、鲍氏不动杆菌(Acinetobacter baumannii)、结核杆菌(Mycobacterium tuberculosis)、耐甲氧西林金黄色葡萄球菌(Methicillin-resistantStaphylococcus aureus,MRSA)及耐万古霉素金黄色葡萄球菌(Vancomycin-resistantStaphylococcus aureus,VRSA)所组成的群组。
根据本发明的一实施例，该微生物生物膜为人类致病细菌或真菌的生物膜。
根据本发明的一实施例，该人类致病细菌或真菌是选自由溶血葡萄球菌(Staphylococcus haemolyticus)、克雷伯氏肺炎菌(Klebsiella pneumoniae)、绿脓杆菌(Pseudomonas aeruginosa)、大肠杆菌(Escherichia coli)、粪肠球菌(Enterococcusfaecalis)、屎肠球菌(Enterococcus faecium)、白色念珠菌(Candida albicans)及金黄色葡萄球菌(Staphylococcus aureus)所组成的群组。
据此，本发明所提供的抗微生物组合物以及相关方法通过其中酰胺化合物及脂肪酸的协同作用，不但能以更少用量的酰胺化合物达到针对抗药性细菌的抗菌效果，更能够有效并快速地根除微生物的持久性细胞及生物膜。
【附图说明】
为使本发明上述及其他目的、特征、优点及实施例更加明显易懂，因此针对附图说明如下：
图1：S.aureus NCTC8325(左上图)和MRSA USA300(右上图)是在暴露于SC5005(4xMIC，1mg/L；实心方块)、DHA(8mg/L；实心倒三角形)、SC5005与DHA(实心三角形)以及万古霉素(VAN；4x MIC，4mg/L；实心圆圈)后所测定，再藉由cfu测定法计算每个暴露期后肉汤中的活菌数，并表示为cfu/mL；图中显示的数据为个别独立的实验的平均值±SD。S.aureusNCTC8325(左下图)和MRSA USA300(右上图)是在PBS中首先使用万古霉素(VAN；16x MIC,16mg/L)处理12小时以触发持久性，接着洗涤细菌细胞后再分别暴露于SC5005(16xMIC，4mg/L；实心方块)、DHA(8mg/L；实心倒三角形)、SC5005与DHA结合(实心三角形)、万古霉素(VAN；16x MIC，16mg/L；实心圆)及达托霉素(DAP；16x MIC，16mg/L；实心星形)所测定，再藉由cfu测定法计算每个暴露期后肉汤中的活菌数，并表示为cfu/mL；图中显示的数据为三个独立实验的平均值±SD(每组n＝3)。由于每个点的标准偏差非常小，故图中并未呈现出误差线。图中的水平虚线代表毒杀99％的细菌细胞。除此之外，图1当中的空白对照皆是以实心菱形表示。
图2：S.aureus NCTC8325(左上图)和MRSA USA300(右上图)的生物膜用浓度递增的空白对照(Mock)、DHA、达托霉素(DAP)、万古霉素(VAN)、SC5005和SC5005与DHA结合处理24小时；收取生物膜中的细菌，并于CAMHB中再培养24小时；接着使用cfu测定法确定活细菌的数量。数据代表个别独立的实验，并显示为平均值±SD(每组n＝3)。ns表示不显著，p>0.05；*表示p<0.05；**表示p<0.01；***表示p<0.001。(左下图)MRSA USA300的生物膜用空白对照(Mock)或者SC5005和80mg/L DHA处理1、3或10分钟，并使用cfu测定法收集和计数生物膜中的活细菌；数据代表个别独立的实验，并显示为平均值±SD(每组n＝3)。ns表示不显著，p>0.05；*表示p<0.05；**表示p<0.01；***表示p<0.001。(右下图)将RAW264.7细胞暴露于空白对照(Mock)或者浓度不断增加的SC5005和80mg/L DHA中10、30或60分钟，并使用MTT测定法确定细胞的活性，再表示为相对于对照组(DMSO和乙醇)处理的细胞的百分比。显示的数据是平均值±SD(每组n＝3)。
【具体实施方式】
术语
本说明书中所使用的通常在本发明的范围内，且每个术语的具体上下文与其在相关领域的一般含义相同。在本说明书中说明本发明时所使用的具体术语，将会在下文或本说明书的其他地方说明，以帮助本领域技术人员理解本发明的相关说明。在同一上下文中，相同术语具有相同的范围和含义。此外，由于表达同一事物的方式不止一种；因此，本说明书中所讨论的术语可以用替代术语和同义词替换，而且在本说明书中是否指定或讨论一个术语并没有任何特殊含义。本说明书虽然提供一些术语的同义词，但是使用一或多个同义词并不表示排除其他同义词的使用。
如本说明书中使用情况，除上下文另有明确说明外，“一”和“该”也可解释为复数。此外，在本说明书及随附专利申请范围中，用以界定本发明的数值范围与参数皆是约略的数值，此处已尽可能精确地呈现具体实施例中的相关数值。然而，任何数值本质上不可避免地含有因个别测试方法所致的标准偏差。在此处，“约”通常是指实际数值在一特定数值或一范围的正负10％、5％、1％或0.5％之内。或者是，“约”一词代表实际数值落在平均值的可接受标准误差之内，是本发明所属领域中具有通常知识者的考量而定。因此，除非另有相反的说明，本说明书与附随申请专利范围所揭示的数值参数皆为约略的数值，且可视需求而更动。至少应将这些数值参数理解为所指出的有效位数与套用一般进位法所得到的数值。再者，说明为便于阅读可能附有标题和副标题，但这些标题并不影响本发明的范围。
如本文所用，术语“组合物”意欲包括包含该等指定成份(若有表示指定量，且为指定量)的产物，以及指定量之从该等指定成份之组合直接或间接形成的任何产物。
如本文所用，术语“脂肪酸”是指由疏水性碳链及亲水性羧基组成的两性分子。碳链中没有双键的脂肪酸被称为饱和脂肪酸，而带有双键的脂肪酸则是不饱和脂肪酸；依据双键数量则可进一步区分为单不饱和脂肪酸及多不饱和脂肪酸。所述双键可为顺式或反式，其导致不同的物理性质。在自然界中，大多数的不饱和脂肪酸为顺式脂肪酸，而反式脂肪酸则大多是经由氢化产生。
如本文所用，术语“酰胺化合物”是指具有通式为R1C(＝O)NR2R3的化合物；其中R1、R2及R3为取代基，其分别可以是氢原子或有机基团。
如本文所用，术语“医药组合物”是表示其包含一活性成分及一医药上可接受的载体；以本案而言，该活性成分是为本发明所提供的抗微生物组合物。详言之，该医药组合物根据需求可包含医药上可接受的赋形剂或稀释剂。
如本文所用，术语“医药上可接受”是指其所指定的稀释剂、赋形剂或载体必须与该调配物的其他成份兼容，且对其接受者无害。
进一步而言，术语“医药上可接受之载体”在本技术领域已受认可且包括适于将本发明抗微生物组合物投予哺乳动物的医药上可接受的材料、组成物或赋形剂。
抗微生物组合物
本发明提供一种抗微生物组合物，其包括：一酰胺化合物；以及一脂肪酸；其中，该脂肪酸是一具有16至22个碳原子的顺式不饱和脂肪酸。
根据本发明一些实施例，该酰胺化合物是丙二酰胺衍生物；较佳地，其是一具有化学结构(I-1)或(I-2)的化合物：
其中R1及R2分别为/> 且R1及R2非同时为/> R3为氢、甲苯、/> R4为氢或氟。
较佳地，R1为 而R2为/>
根据本发明一些实施例，该酰胺化合物是一含尿素(碳酰胺)化合物；较佳地，其是二苯基脲的类似物。具体而言，该酰胺化合物是一具有化学结构(II)的化合物：
其中R1为
R2为
较佳地，该酰胺化合物是具有化学结构(III)至(VII)中任一者的化合物：
根据本发明一些实施例，该脂肪酸是一具有16至22个碳原子的顺式单不饱和脂肪酸或顺式多不饱和脂肪酸。具体而言，该脂肪酸具有16、17、18、19、20、21或22个碳原子。较佳地，该脂肪酸是一棕榈油酸、油酸、亚油酸、α-亚油酸、花生四烯酸、二十碳五烯酸或二十二碳六烯酸。
根据本发明一些较佳的实施例，该脂肪酸的含量大于该酰胺化合物的含量。
医药组合物及用途
医药组合物
本发明之医药组合物包含上述抗微生物组合物以及至少一医药上可接受的载体。根据需求，该医药组合物可包含医药上可接受的赋形剂或稀释剂。
该医药上可接受载体包括液态或固态填料、稀释剂、赋形剂、溶剂或胶囊材料，其牵涉到将活性成分从一个器官或身体一部分携带或输送至另一器官或身体的另一部分。各种载体必须是在可与调配物其他成份兼容且不伤病患之意义上而“可接受”者。作为医药上可接受的载体的某些实例包括：糖类，诸如乳糖、葡萄糖与蔗糖；淀粉类，诸如玉米淀粉与马铃薯淀粉；纤维素与其衍生物，诸如羧甲基纤维素钠、乙基纤维素与乙酸纤维素；粉末状黄蓍树胶；麦芽；明胶；滑石；赋形剂，诸如可可脂与栓剂蜡；油类，诸如花生油、棉籽油、红花子油、芝麻油、橄榄油、玉米油与大豆油；二醇类，诸如丙二醇；多元醇类，诸如甘油、山梨醇、甘露醇与聚乙二醇；酯类，诸如油酸乙酯与月桂酸乙酯；琼脂；缓冲剂，诸如氢氧化镁与氢氧化铝；褐藻酸；无热原质水；等渗压盐水；林格氏溶液；乙醇；磷酸盐缓冲溶液；以及其他用于药学调配物中无毒性可相同物质。
湿润剂、乳化剂与润滑剂(诸如月桂基硫酸钠与硬脂酸镁)以及着色剂、脱模剂、涂覆剂、甜味剂、调味与加香剂、防腐剂与抗氧化剂亦可存在该医药组合物中。
医药上可接受之抗氧化剂实例包括：水溶性抗氧化剂，诸如抗坏血酸、盐酸半胱胺酸、硫酸氢钠、偏亚硫酸氢钠、亚硫酸氢钠等；油溶性抗氧化剂，诸如棕榈酸抗坏血酸酯、丁基羟基甲氧苯(BHA)、二丁基经基甲苯(BHT)、卵磷脂、五倍子酸丙酯、α-生育酚等；以及金属螯合剂，诸如柠檬酸、乙二胺四乙酸(EDTA)、山梨醇、酒石酸、磷酸等。
本发明的医药组合物包括适于口服、鼻腔、局部、经皮、经颊、舌下、直肠、阴道及/或非经肠投药者。该医药组合物可便利地以单位剂量形式存在，且可以药学技术中任何为人熟知的方法制备。可与载体材料结合以制造单一剂量形式的活性成份之量通常为产生疗效的量。通常，每100％中，该量为约1％至约99％活性成份，较佳为约5％至约70％，最佳为约10％至约30％。
制备该医药组合物的方法包括结合本发明抗微生物组合物与载体，及随意地一或多种辅助成份。通常，该医药组合物是藉由均匀且紧密结合本发明组合物与液态载体或细碎的固态载体或此二者，然后视需要令该产物成形而制备。
适于口服投药可为胶囊、扁囊剂、丸剂、锭剂(使用经调味主药，通常为蔗糖与阿拉伯树胶或黄蓍树胶)、粉剂、小颗粒，或为在水性或非水性液体中之溶液或悬浮液，或为水包油型或油包水型液态乳液，或为酏剂或糖浆，或为软锭剂(使用惰性基质，诸如明胶与甘油，或蔗糖与阿拉伯树胶)及/或为潄口水等形式，各含有预定量之本发明抗微生物组合物作为活性成份。本发明之医药组合物亦可以球剂、舐剂或糊剂投药。
在本发明的口服投药的固态剂量形式(胶囊、锭剂、丸剂、糖衣锭、粉剂、小颗粒等)中，该活性成份是与一或多种医药上可接受的载体混合，该等载体是诸如柠檬酸钠或磷酸二钙及/或下列任一者：填料或增量剂，诸如淀粉、乳糖、蔗糖、葡萄糖、甘露醇及/或硅酸；黏合剂，诸如接甲基纤维素、褐藻酸酯、明胶、聚乙烯四氢吡咯酮、蔗糖及/或阿拉伯树胶；保湿剂，诸如甘油；崩解剂，诸如琼脂、碳酸钙、马铃薯或树薯淀粉、褐藻酸、特定硅酸盐，与碳酸钠；溶液滞凝剂，诸如石蜡；吸收促进剂，诸如四级铵化合物；湿润剂，诸如鲸蜡醇与一硬脂酸甘油酯；吸收剂，诸如高岭土与膨土；润滑剂，诸如滑石、硬脂酸钙、硬脂酸镁、固态聚乙二醇、月桂基硫酸钠与其混合物，以及着色剂。在胶囊、锭剂与丸剂情况下，该药学组成物亦可包含缓冲剂。相似类型之固态组成物亦可作为使用赋形剂(诸如乳糖(lactose)或乳糖(milk sugar)以及高分子量聚乙二醇等)之软与硬填充明胶胶囊的填料。
锭剂可通过随意地与一或多种辅助成份压缩或模制而制得。压缩锭剂可使用黏合剂(例如明胶或羟丙基甲基纤维素)、润滑剂、惰性稀释剂、防腐剂、崩解剂(例如淀粉羟乙酸钠或交联羧甲基纤维素钠)、表面活性或分散剂。模制锭剂可藉由在适用机器中模制以惰性液态稀释剂湿润的粉末状化合物的混合物而制得。
该等锭剂与本发明医药组合物的其他固态剂量形式(诸如糖衣锭、胶囊、丸剂与小颗粒)可随意地划痕或制备涂层与外壳，诸如肠溶涂层与制药技术中广为人知之其他涂层。彼等亦可使用例如不同比例以提供所需之释放曲线之羟丙基甲基纤维素、其他聚合物基质、脂质体及/或微球体加以调配，以便提供缓慢或受控制释放其中之活性成份。彼等可藉由例如经由保留细菌之过滤器过滤、或藉由混入呈可溶解在灭菌水中之灭菌固态组成物形式的灭菌剂，或某些其他在使用前可注入之灭菌介质而灭菌。医药组合物亦可随意地含有乳浊剂，且可为仅在或较佳是在肠胃特定部分中随意地以延缓方式释放该(等)活性成份。可使用的包埋组成物实例包括聚合物质与蜡。该活性成份亦可呈微胶囊化形式，若情况适当，具有一或多种上述赋形剂。
本发明医药组合物的口服投药用液态剂量形式包括药学上可接受的乳液、微乳液、溶液、悬浮液、糖浆与酏剂。除了活性成份之外，该液态剂量形式可含有本技术中常用的惰性稀释剂，诸如水或其他溶剂、助溶剂与乳化剂，诸如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苯甲酯、丙二醇、1,3-丁二醇、油类(特别是棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油与芝麻油)、甘油、四氢呋喃醇、聚乙二醇与山梨醇酐之脂肪酸酯，以及其混合物。除了惰性稀释剂之外，该口服组成物亦可包括佐剂，诸如湿润剂、乳化与悬浮剂、甜味剂、调味剂、着色剂、香料与防腐剂。除了该等活性化合物之外，悬浮液可含有悬浮剂，例如乙氧基化异硬脂醇、聚氧乙烯山梨醇与山梨醇酐酯、微结晶纤维素、偏氢氧化铝、膨土、琼脂与黄蓍树胶，及其混合物。
供直肠或阴道投药的本发明医药组合物的调配物可呈栓剂状，其可藉由混合一或多种本发明之化合物与一或多种适用之非刺激性赋形剂或载体而制备，该等赋形剂或载体包含例如可可脂、聚乙二醇、栓剂蜡或水杨酸酯，且其在室温下呈固态但在体温下呈液态，因此会在直肠或阴道腔中熔融并释放该活性化合物。适用于阴道投药之本发明调配物亦包括含有如本技术领域中习知适当之载体的阴道栓剂、棉塞、乳霜、凝胶、糊剂、泡沫或喷雾调配物。
本发明医药组合物的局部或经皮投药的剂量形式包括粉剂、喷雾、油膏、糊剂、乳霜、洗剂、凝胶、溶液、贴布与吸入剂。本发明之抗微生物组合物可在灭菌条件下与医药上可接受之载体，及与任何可能需要之防腐剂、缓冲剂或推进剂混合。除了活性成分之外，该油膏、糊剂、乳霜与凝胶可含有赋形剂，诸如动物与植物脂肪、油、蜡、石蜡、淀粉、黄蓍树胶、纤维素衍生物、聚乙二醇、聚硅氧、膨土、硅酸、滑石与氧化锌，或其混合物。
经皮贴片具有提供受控制输送本发明的抗微生物组合物至身体的附加优点。此种剂量形式可藉由将该组合物溶解或分散于适当介质中而制得。亦可使用吸收加强剂以提高该化合物穿过皮肤的通量。此种通量率可藉由提供速率控制薄膜或将该组合物分散在聚合物基质或凝胶中而加以控制。
眼科调配物、眼用油膏、粉剂、溶液等也被视为在本发明范围内。
适于非经肠投药的本发明医药组合物包含一或多种本发明的抗微生物组合物与一或多种医药上可接受的灭菌等渗压水性或非水性溶液、分散液、悬浮液或乳液，或可在使用前才重新组成灭菌注射溶液或分散剂的灭菌粉末，其可含有抗氧化剂、缓冲剂、抑菌剂、可使该调配物与计划中之受试对象的血液等渗压之溶质，或悬浮剂或增稠剂。
可用于本发明医药组合物的适用水性与非水性载体实例包括水、乙醇、多元醇(诸如甘油、丙二醇、聚乙二醇等)与其适用混合物、植物油(诸如橄榄油)与可注射有机酯(诸如油酸乙酯)。适当流性可通过例如使用涂覆材料(诸如卵磷脂)、在分散液情况下通过维持所需的粒子大小，以及通过使用界面活性剂而加以维持。
医药组合物也可含有佐剂，诸如防腐剂、湿润剂、乳化剂与分散剂。藉由包括各种抗菌与抗霉菌剂(例如对羟苯甲酸酯、氯丁醇、酚山梨酸等)而确保避免微生物的作用。亦可能需要将等渗压剂，诸如糖、氯化钠等包括入该组成物。此外，可通过包括延缓吸收的药剂(诸如一硬脂酸铝与明胶)而使注射药学形式具有长期吸收性。
在一些实施例中，为了延长药物之效果，需要减缓从皮下或肌内注射的药物的吸收。此可以藉由使用具有不良水溶性之结晶或非晶材料的液态悬浮液而达成。然后，该药物的吸收速率是视其溶解速率而定，因此可视结晶大小与结晶形而定。或者，非经肠投药之药物形式的延缓吸收可藉由将该药物溶解或悬浮在油性赋形剂中而达成。
注射贮存形式(injectable depot form)可藉由将本发明医药组合物的微胶囊基质形成于可生物降解聚合物(诸如聚丙交酯-聚乙交酯)中而制得。药物释放速率可视药物对聚合物的比率以及所使用的特定聚合物的性质而加以控制。其他可生物降解聚合物的实例包括聚(原酸酯)与聚(酐)。贮存注射调配物亦可藉由将该药物裹于与体组织可兼容之脂质体或微乳液中而制备。
不论所选用投药途径为何，本发明之抗微生物组合物(其可以适用水合形式使用)及/或本发明之医药组合物是藉由本领域技术人员习知的惯用方法调配成药学上可接受之剂量形式。
本发明医药组合物中的活性成份的实际剂量水平可改变，以便获得对病患无毒性的有效致特定病患所需的治疗反应的活性成份之量、组成物，与投药模式。
该选用剂量水平会视各式因素而定，该等因素包括本发明所使用之特定化合物或其酯、盐或酰胺的活性、投药途径、投药时间、所使用之特定化合物的排泄速率、治疗持续时间、与所使用特定化合物并用之其他药物、化合物及/或材料、接受治疗之病患之年龄、性别、体重、状态、一般健康、与先前病史等医药技术中为人熟知的因素。
具有本技术领域中具有通常知识之医生或兽医可迅速判定并指示所需医药组合物的有效量。例如，该医生或兽医可以低于获得所需治疗效果所需之水平作为该医药组合物中所使用的本发明化合物剂量开始，并逐渐提高该剂量直到获致所需效果为止。
用途
本发明进一步提供上述抗微生物组合物的用途，其用于制备用于抑制微生物细胞以及微生物生物膜生长的药剂。
根据本发明一些实施例，该微生物细胞为人类致病菌的细胞。更具体而言，该人类致病菌是选自由金黄色葡萄球菌、溶血葡萄球菌(S.haemolyticus)、人葡萄球菌(S.hominis)、中间葡萄球菌(S.intermedius)、腐生葡萄球菌(S.saprophyticus)、路邓葡萄球菌(S.lugdunesis)、猪红斑丹毒丝菌(Erysipelothrix rhusiopathiae)、粪肠球菌(Enterococcus faecalis)、屎肠球菌(Enterococcus faecium)、万古霉素抗性屎肠球菌(VR-E.faecium)、蜡样芽孢杆菌(Bacillus cereus)、枯草芽孢杆菌(Bacillus subtilis)、白喉杆菌(Corynebacterium diphtheriae)、李斯特单胞菌(Listeria monocytogenes)、酿脓链球菌(Streptococcus pyogenes)、困难梭状芽孢杆菌(Clostridium difficile)、大肠杆菌(Escherichia coli)、鼠伤寒沙门杆菌(Salmonelia Typhimurium)、鲍氏不动杆菌(Acinetobacter baumannii)、结核杆菌(Mycobacterium tuberculosis)、耐甲氧西林金黄色葡萄球菌(Methicillin-resistant Staphylococcus aureus,MRSA)及耐万古霉素金黄色葡萄球菌(Vancomycin-resistant Staphylococcus aureus,VRSA)所组成的群组。
根据本发明一些实施例，该微生物生物膜为人类致病细菌或真菌的生物膜。更具体而言，该人类致病细菌或真菌是选自由溶血葡萄球菌(Staphylococcus haemolyticus)、克雷伯氏肺炎菌(Klebsiella pneumoniae)、绿脓杆菌(Pseudomonas aeruginosa)、大肠杆菌(Escherichia coli)、粪肠球菌(Enterococcus faecalis)、屎肠球菌(Enterococcusfaecium)、白色念珠菌(Candida albicans)及金黄色葡萄球菌(Staphylococcus aureus)所组成的群组。
实施例
在本节中，将通过以下实施例来详细说明本发明的内容。这些案例仅作为说明之用，而本案所属技术领域具有通常知识者得以很容易知悉各种修改例和变化例。因此，下面将详细说明本发明的各种实施例，然而本发明并不限于本说明书中列出的该各种实施例。
材料与方法
细胞
将老鼠巨噬细胞RAW264.7(BCRC)以及人类子宫颈上皮癌细胞HeLa(BCRC)培养在含有10％加热非活化的FBS(Gibco-BRL)的Dulbecco改良培养基(DMEM；Gibco-BRL)中。人类胚胎肾细胞HEK-293(BCRC)及永生化的非致瘤性角质形成细胞HaCaT(来自台湾大学的Yung-Chiy Chang博士)培养在添加10％加热非活化FBS的RPMI培养基(RPMI；Gibco-BRL)中。细胞在75T细胞培养瓶中以37℃和5％CO2环境中培养。
试剂
将酰胺化合物样本合成并溶解在DMSO中以产生储备溶液(10g/L)。将氨芐青霉素(10g/L；USB)、苯唑西林(10g/L；Sigma-Aldrich)、氧氟沙星(1g/L；Bio Basic)及万古霉素(10g/L；GoldBio)溶解于无菌去离子水中制备储备溶液。花生四烯酸、二十碳五烯酸、反油酸、芥酸、贡多酸、α-亚麻酸、亚油酸、肉荳蔻油酸、神经酸、油酸、棕榈油酸及硬脂酸是购自Cayman Chemical，皆溶于95％乙醇中以制成储备溶液(10g/L)。将二十二碳六烯酸(DHA，40g/L；Santa Cruz)、红霉素(10g/L；Bio Basic)和四环素(10g/L；Bio Basic)溶解在95％乙醇中制成储备溶液。将环丙沙星(10g/L；Sigma-Aldrich)、达托霉素(10g/L；Sigma-Aldrich)、利奈唑胺(10g/L；Santa Cruz)、利福平(10g/L；Bio Basic)及索拉非尼(10g/L；拜耳制药公司友情提供)溶解在DMSO中制成储备溶液。
抗菌活性测定
于此，抗菌活性是基于MIC以及MBC二指标；MIC是指最低抑菌浓度(minimuminhibitory concentration)，而MBC是指最低杀菌浓度(minimum bactericidalconcentration)。于此根据CLSI指南使用微量肉汤稀释法测定个别试剂对MRSA USA300菌株的MIC。简言之，将LB培养基中的过夜细菌培养物在新鲜LB培养基中以1:50稀释，并在37℃下培养直至达到OD600为0.5至0.6。将细菌悬浮液在新鲜CAMHB中稀释至最终浓度为5*105cfu/mL，然后在37℃下在96孔板中以增加剂量一式三份暴露于每种测试剂24小时。每种药剂的MIC定义为不具可见细菌生长的最低浓度。MBC则是藉由在CAMHB琼脂板上以37℃继代培养5μL等于或高于MIC的稀释度的肉汤稀释液24小时所测定的；MBC的定义为不具活细菌的最低肉汤稀释度。
为了评估脂肪酸对酰胺化合物的抗菌活性的影响，将细菌悬浮液在含有指定浓度脂肪酸的新鲜CAMHB中稀释至最终浓度为5*105cfu/mL；接着使用上述方案测定个别药剂的MIC和MBC。然后，通过计算它们相应的分数抑制浓度指数(FICI)来测量每种组合的协同作用，公式为ΣFIC(FICi)＝FICA+FICB＝(CombA/MICA)+(CombB/MICB)，其中MICA和MICB分别为A药和B药单独的MIC，CombA及CombB分别为A药和B药组合的浓度。具有协同作用定义为FICI≤0.5；无相互作用定义为0.5<FICI≤4.0，拮抗作用定义为FICI>4。
抗增殖试验
利用3-(4,5-二甲基噻唑-2-基)-2,5-二苯基-2H-溴化四唑(MTT)测定法评估酰胺化合物及脂肪酸对哺乳动物细胞活性的影响，每个实验组重复6次。简而言之，将细胞以每孔104个细胞接种到96孔盘中，培养24小时，然后暴露于浓度范围为5-30mg/L的酰胺化合物或酰胺化合物与脂肪酸组合24小时。对照组使用与实验组处理细胞相同浓度的DMSO及乙醇。处理结束时，将培养基更换为含0.5g/L MTT的培养基，将细胞在CO2培养箱中于37℃再培养1.5小时。从孔中取出上清液，将还原的MTT染料溶解在DMSO中，接着使用VersaMax微量盘检测仪(Molecular Devices，USA)测量每个孔在570nm处的吸光值。
持久性细胞消除试验
将对数期细菌调整至OD600＝0.2，然后在37℃下用16×MIC的万古霉素处理12小时。在4℃下以4000×g离心10分钟收集细菌，用冰冷的PBS洗涤，并将测试试剂悬浮在PBS中。对照组用与药物处理细菌相同浓度的DMSO和乙醇处理。在指定时间，在PBS中连续稀释100μL等分细菌悬浮液，然后将其涂抹在LB琼脂板上以评估活细菌的数量。在37℃培养18-24小时后，计数菌落数是以cfu/mL表示。
生物膜清除试验
如上所述，评估达托霉素、万古霉素、实验酰胺化合物及实验酰胺化合物与脂肪酸组合对微生物的生物膜的根除活性。简而言之，细菌在胰蛋白酶大豆肉汤(BectonDickinson，美国)中生长，并在96孔盘以5x105cfu/mL浸没在细菌培养物中的盖子的钉子上形成生物膜。24小时后，用PBS洗涤钉子两次，然后转移到新的96孔盘中，每个孔中含有浓度范围为0.125mg/L至1024mg/L的测试试剂。在37℃下培养24小时后，洗涤钉盖，将其置于新的96孔盘中，每孔装有新鲜的CAMHB，并以超音波处理5分钟以破坏钉子上的生物膜，接着利用cfu测定法检测每个孔中的活细菌以评估数量。同时，为了确定最低生物膜清除浓度，将96孔盘盖上新盖并在37℃下培养24小时，然后使用cfu测定法对每个孔中的活细菌进行计数。
统计分析
数据表示为平均值±SD。使用Prism软件(v6.0，GraphPad，USA)以单因素方差分析和Dunnett比较计算组平均值之间的差异，并且P值<0.05则为显著差异。
结果
酰胺化合物与各式脂肪酸结合的协同作用
于此采用的酰胺化合物为SC5005(结构如下文所示)，其与不同脂肪酸结合使用，并进一步测定其结合后对于MRSA USA300菌株的抗菌活性；结果如表1及表2，分别呈现SC5005与不同脂肪酸结合后对于MRSA USA300菌株之MIC及MBC。
SC5005之结构：
表1
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表2
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表1及表2当中，单个脂肪酸的结构用CA:DnEF的形式表示，其中A是碳原子数，D是双键数，E是从甲基端到双键中最接近甲基末端的第一个碳的碳数，F表示双键的几何性质(c：顺式或t：反式)。通过计算相应的分数抑制浓度指数(FICI)来测量组合效果。协同作用(Syn)定义为FICI≤0.5，无相互作用(NI)定义为FICI>0.5且≤4.0，拮抗作用(Ant)定义为FICI>4。
根据表1及表2可见，SC5005与顺式不饱和脂肪酸有协同作用。详言之，尽管与油酸具有相同的碳链长度，然而饱和硬脂酸(C18:0)与SC5005对MRSA USA300并未显示协同作用；反油酸(C18:1n9t)也具有18个碳原子，然而同时具有一个反式双键，故亦未显示协同作用。据此可见，顺式双键对于酰胺化合物及脂肪酸的协同抗菌性相当重要。另一方面，表1及表2的结果显示，SC5005及16碳顺式单不饱和脂肪酸棕榈油酸(C16:1n7c)的结合具有协同作用；20碳及22碳顺式单不饱和脂肪酸贡多糖酸(C20:1n9c)及芥酸(C22:1n9c)分别与SC5005显示出协同性的杀菌作用，然而对于MIC没有影响。又，24碳神经酸(C24:1n9c)及14碳肉荳蔻脑酸(C14:1n5c)皆未显示与SC5005的任何协同活性。据此，SC5005与碳链长为16至22个碳原子范围内的顺式不饱和脂肪酸具有协同抗菌活性。
接续，SC5005与亚油酸(C18:2n6c)结合的抗菌活性优于油酸(C18:1n9c)及α-亚油酸(C18:3n3c)。另，虽然花生四烯酸(C20:4n6c)及二十碳五烯酸(C20:5n3c；EPA)具有不同数量的双键，然而两者对SC5005抗菌活性的影响是相同的。由此可见，不饱和脂肪酸碳链中双键的数量与其与SC5005的协同抗菌活性无关。
脂肪酸与各式酰胺化合物的协同作用
于此呈现不同酰胺化合物结合固定浓度的脂肪酸时，对于MRSA USA300菌株的抗菌活性变化；其中所采用的脂肪酸为二十二碳六烯酸(DHA)，结果如表3所示。
表3
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由表3的内容可见，多个酰胺化合物样本皆与DHA有协同的抗菌活性(亦即加入DHA之后的MIC小于其原本之MIC的1/4)，包括索拉非尼、PK150及其相似物等。
组合物对于耐抗生素金黄色葡萄球菌的抗菌活性
本实施例的组合物的酰胺化合物是采用索拉非尼、SC5005以及PK150，而其脂肪酸是采用DHA。于此评估SC5005与DHA的组合物对一系列耐抗生素金黄色葡萄球菌菌株的抗菌活性；结果如表4所示。
表4
表4中，AMP是指氨芐青霉素(ampicillin)；ERY是指红霉素(erythromycin)；OXA是指苯唑西林(oxacillin)；TET是指四环素(tetracycline)；OFX是指氧氟沙星(ofloxacin)；CIP是指环丙沙星(ciprofloxacin)；LZD是指利奈唑胺(linezolid)；RIF是指立汎霉素(rifampicin)；VAN是指万古霉素(vancomycin)。
根据表4的内容，尽管对于各式抗生素具有抗药性，然而所有测试的细菌菌株对于单独DHA及单独SC5005皆分别表现出相同的敏感性，MIC分别为1024mg/L和0.25mg/L。相对之下，即便个别菌株对SC5005及DHA的组合物的敏感性不尽相同，然而整体结果显示SC5005和DHA的组合物对所有测试的细菌菌株皆显示出协同抗菌作用。
组合物对于哺乳动物细胞的细胞毒性
于此，本发明人采用SC5005作为酰胺化合物，并采用DHA作为脂肪酸，进一步评估了SC5005在DHA浓度不断升高的情况下对四种不同哺乳动物细胞系的抗增殖活性；结果如表5所示。所述哺乳动物细胞为老鼠巨噬细胞(RAW264.7)、人类子宫颈癌上皮细胞(HeLa)、人类角质形成细胞(HaCaT)以及人类肾胚胎细胞(HEK-293)。由表5可见，即便在存在16mg/LDHA的情况下，SC5005对各个细胞系的细胞毒性亦未有显著变化。据此，该结果显示本发明之组合物的协同作用是针对病原菌，而不会对哺乳动物细胞造成伤害。
表5
组合物消除持久性细胞
于此，本发明人评估SC5005、DHA及其组合对金黄色葡萄球菌NCTC8325及MRSAUSA300的杀菌动力学(time-kill kinetics)；结果如图1所示。由图1可见，SC5005在24小时内杀死了超过99.9％的细菌。相较之下，8mg/L的DHA在治疗初期仅对金黄色葡萄球菌NCTC8325的生长有中度抑制作用，随后细菌生长反弹至与对照组相同的程度。值得注意的是，SC5005和DHA的结合在10分钟内完全消灭了所有细菌，表示SC5005和DHA的协同抗菌活性具有很强的杀菌作用。另一方面，金黄色葡萄球菌可以进入非生长状态(即所谓的持久性细胞)，并对抗生素治疗产生耐受性而导致细菌反覆感染。为了分离出金黄色葡萄球菌持久性细胞，我们在PBS缓冲液中以杀菌浓度的抗生素万古霉素处理12小时以消除非持久性细胞。如图所示，剩余的细菌细胞对万古霉素和另一种杀菌抗生素达托霉素的杀伤活性具有耐受性，表示这种细菌细胞亚群由持久性细胞组成。再次参照图1可见，SC5005及其与DHA的结合在杀死持久细胞方面非常有效，并且持久性细胞分别在24小时和30分钟内被根除。此一发现显示SC5005和DHA结合的作用机制(MoA)与细菌代谢活动无关。
组合物清除金黄色葡萄球菌生物膜
当金黄色葡萄球菌附着在医疗植入物或宿主组织上时，它可以建立生物膜，提供有利于形成持久性细胞的环境，并且通常与慢性感染和治疗失败有关。为了确定SC5005和DHA可以根除金黄色葡萄球菌生物膜，本发明人单独使用浓度递增的SC5005或者与8mg/LDHA一并处理细菌生物膜24小时；结果如图2所示。根据图2之内容，SC5005与达托霉素和万古霉素相比表现出优异的生物膜清除活性。然而，8mg/L DHA并没有增强SC5005的生物膜根除活性，甚至对MRSA USA300生物膜有拮抗作用；这表示主要由多糖、蛋白质和核酸组成的生物膜基质可能会干扰SC5005和DHA的协同作用。接着将DHA的浓度提高到80mg/L，便观察到SC5005的生物膜根除活性增加了32倍。除此之外，由图2亦可见，1mg/L SC5005和80mg/LDHA的结合在1分钟内去除了生物膜中近99％的细菌，且在长达60分钟内对RAW264.7细胞未产生可检测到的细胞毒性。总体来说，与二线抗生素相比，SC5005和DHA的结合对金黄色葡萄球菌生物膜均表现出优异和快速的杀菌活性。
本发明具体实施例已经揭露，但并非旨在限制本发明。本案所属技术领域具有通常知识者均能够理解，在未偏离本发明原理和精神的情况下，可以做出各种变更例和修饰例，因此本发明的保护范围应当以随附的权利要求书中所限定的范围为基础。
Claims (14)
1.一种抗微生物组合物，其包括：
酰胺化合物；以及
脂肪酸；
其中，所述脂肪酸是一具有16至22个碳原子的顺式不饱和脂肪酸。
2.如权利要求1所述的抗微生物组合物，其中所述酰胺化合物是一具有化学结构(I-1)或(I-2)的化合物：
其中R1及R2分别为 且R1及R2非同时为/>
R3为氢、甲苯、R4为氢或氟。
3.如权利要求2所述的抗微生物组合物，其中R1为
而R2为/>
4.如权利要求1所述的抗微生物组合物，其中所述酰胺化合物是一具有化学结构(II)的化合物：
其中R1为
R2为
5.如权利要求1所述的抗微生物组合物，其中所述酰胺化合物是具有化学结构(III)至(VII)中任一者的化合物：
6.如权利要求1所述的抗微生物组合物，其中所述脂肪酸是一具有16至22个碳原子的顺式单不饱和脂肪酸或顺式多不饱和脂肪酸。
7.如权利要求1所述的抗微生物组合物，其中所述脂肪酸是一棕榈油酸、油酸、亚油酸、α-亚油酸、花生四烯酸、二十碳五烯酸或二十二碳六烯酸。
8.如权利要求1所述之抗微生物组合物，其中所述脂肪酸的含量大于所述酰胺化合物的含量。
9.一种医药组合物，其包含如权利要求1至8中任一项的抗微生物组合物以及至少一医药上可接受的载体。
10.一种如权利要求1至8中任一项抗微生物组合物的用途，其用于制备用于抑制微生物细胞以及微生物生物膜生长的药剂。
11.如权利要求10所述的用途，其中所述微生物细胞为人类致病菌的细胞。
12.如权利要求11所述的用途，其中所述人类致病菌是选自由金黄色葡萄球菌、溶血葡萄球菌(S.haemolyticus)、人葡萄球菌(S.hominis)、中间葡萄球菌(S.intermedius)、腐生葡萄球菌(S.saprophyticus)、路邓葡萄球菌(S.lugdunesis)、猪红斑丹毒丝菌(Erysipelothrix rhusiopathiae)、粪肠球菌(Enterococcus faecalis)、屎肠球菌(Enterococcus faecium)、万古霉素抗性屎肠球菌(VR-E.faecium)、蜡样芽孢杆菌(Bacillus cereus)、枯草芽孢杆菌(Bacillus subtilis)、白喉杆菌(Corynebacteriumdiphtheriae)、李斯特单胞菌(Listeria monocytogenes)、酿脓链球菌(Streptococcuspyogenes)、困难梭状芽孢杆菌(Clostridium difficile)、大肠杆菌(Escherichia coli)、鼠伤寒沙门杆菌(Salmonelia Typhimurium)、鲍氏不动杆菌(Acinetobacter baumannii)、结核杆菌(Mycobacterium tuberculosis)、耐甲氧西林金黄色葡萄球菌(Methicillin-resistant Staphylococcus aureus,MRSA)及耐万古霉素金黄色葡萄球菌(Vancomycin-resistant Staphylococcus aureus,VRSA)所组成的群组。
13.如权利要求10所述的用途，其中所述微生物生物膜为人类致病细菌或真菌的生物膜。
14.如权利要求13所述的用途，其中所述人类致病细菌或真菌是选自由溶血葡萄球菌(Staphylococcus haemolyticus)、克雷伯氏肺炎菌(Klebsiella pneumoniae)、绿脓杆菌(Pseudomonas aeruginosa)、大肠杆菌(Escherichia coli)、粪肠球菌(Enterococcusfaecalis)、屎肠球菌(Enterococcus faecium)、白色念珠菌(Candida albicans)及金黄色葡萄球菌(Staphylococcus aureus)所组成的群组。
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