CN110227145A - 抗菌蛋白 - Google Patents
抗菌蛋白 Download PDFInfo
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- CN110227145A CN110227145A CN201910628294.5A CN201910628294A CN110227145A CN 110227145 A CN110227145 A CN 110227145A CN 201910628294 A CN201910628294 A CN 201910628294A CN 110227145 A CN110227145 A CN 110227145A
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Abstract
本发明提供了一种包含含有Blad或其活性变体的抗菌多肽的组合物,用于通过治疗或预防手段对人或动物体治疗的方法中,例如用于被微生物感染的个体体内或体表的治疗或预防的方法。本发明还提供了一种包含含Blad或其活性变体的抗菌多肽的组合物的应用,用以杀死或抑制对人类或动物致病的微生物的生长,该作用位点不在人或动物体体内或体表。
Description
本申请是中国专利申请号201180049655.2,申请日2011年10月12日,发明名称为“抗菌蛋白”的分案申请。
技术领域
本发明涉及抗菌剂领域,特别是作用于人或动物的病原体的抗菌剂。
背景技术
细菌感染
细菌是至今为止最普遍的人类感染的病因。全球大于三分之一的人口有可能被细菌性病原体感染,并且每年两百万人死于细菌性病原体感染。根据疾病控制中心(CDC)和世界健康组织(WHO)的记载,现今全球最普遍的感染性疾病包括以下细菌感染:
霍乱:该疾病主要通过被污染的饮用水和不卫生条件进行传播。该疾病是印度次大陆,俄罗斯,和南撒哈拉非洲的地方性疾病,它是一种霍乱弧菌(Vibrio cholerae)引起的急性肠道感染病。其主要症状是大量腹泻。5%到10%的感染者会呈现严重症状,包括呕吐和腿痛性痉挛。在这些严重的表现症状中,霍乱会导致脱水致死。每年世界健康组织(WHO)约有200,000例相关报道。
脑膜炎:也称为脊膜炎,这是一种脊髓感染疾病。通常是由病毒或细菌感染的结果。细菌性脑膜炎比病毒性脑膜炎更为严重,并可能引发大脑损伤,听力损失,以及学习障碍。该疾病可能是由以下细菌引起,比如,B型流感嗜血杆菌(Haemophilus influenzae),脑膜炎奈瑟菌(Neisseria meningitidis),或肺炎链球菌(Streptococcus pneumoniae)。每年约有120万个细菌性脑膜炎病例,其中死亡率大于十分之一。症状包括剧烈头痛,高烧,恶心,呕吐,嗜睡,谵妄,畏光,和僵颈。
肺炎:该疾病有许多可能病因,但通常是链球菌或支原体细菌感染。这些细菌可以在人体内存活若干年而不引发感染,并仅在其他疾病降低了人体对疾病的免疫力的时候显现出来。最普遍的类型是肺炎链球菌(Streptococcus pneumoniae)引发的比支原体性肺炎更为严重的链球菌性肺炎。每年高于100,000的肺炎住院治疗是由肺炎链球菌(S.pneumoniae)引起的,以及6,000,000的中耳炎和高于60,000的侵袭性疾病比如脑膜炎也是由链球菌性肺炎引起的。
志贺杆菌病:该感染每年全球大约引发600,000例死亡。在卫生条件欠佳的发展中国家非常普遍。志贺杆菌可以引起细菌性痢疾,或志贺杆菌病。症状包括伴有血便的痢疾,呕吐,以及腹绞痛。
脓毒性咽喉炎:该疾病是由链球菌引起。每年会发生数百万例脓毒性咽喉炎。其症状包括咽喉肿痛,高烧,头痛,疲劳,以及恶心。
结核病:该疾病每年引起将近两百万死亡例,根据WHO预计,在2000到2020年之间,如果不采取更有效的预防措施,将会有近十亿人感染该病。结核杆菌(比如分枝杆菌(Mycobacterium tuberculosis))最常发现于肺中,可以引发胸部疼痛以及引起血痰的剧烈咳嗽。其他症状包括疲劳,体重减轻,食欲不振,寒战,高烧,以及盗汗。
伤寒:伤寒热是由伤寒杆菌引起,每年在12,000,000-17,000,000个病例中,大约有600,000例死亡例。该疾病通常通过感染的食物或水传播。其症状包括突然和持续高烧,剧烈头痛,恶心,严重食欲不振,便秘,以及有时会有腹泻。
但是,准确的病例数量难以确定,尤其是多数该类疾病是发展中国家的地方性疾病,许多人无法得到现代医疗。每年由感染性疾病引起的死亡中,其中大约一半仅是由三种疾病引起:结核病,疟疾,以及艾滋病。总之,这些疾病每年引起超过300,000,000例病患并导致超过5,000,000例死亡。
现代时期抗生素的使用始于19世纪和20世纪早期,伴随由青霉(Penicilliumnotatum)产生的具有有效的抗菌活性的青霉素活性成分的鉴定而产生。但是,在1955年之前,其销售未受控制,过度无控制的使用导致耐药菌的出现。抗生素耐药性便成为主要问题,葡萄球菌耐药感染流行病开始在医院中出现。
20世纪早期已经可见抗生素的发展,比如磺胺,链霉素,新霉素,氯霉素,头孢菌素,以及四环素。许多这些化合物至今仍在使用,但所有这些抗生素都面临抗药性发展的挑战,以及其中一些面临存在毒性问题。例如,链霉素会引起肾脏损伤和耳聋,而氯霉素会引起严重的副作用(比如,严重的血液疾病,包括贫血和白血病)。
对抗生素的进一步研究发生于上世纪60年代,导致了第二代抗生素的发展。其中包括青霉素的半合成衍生物甲氧西林,这是特别针对青霉素的耐药性问题而生产的。甲氧西林被誉为对抗青霉素细菌耐药性战争中的一个主要突破,但是不幸的是,事实并非如此,现在已经存在耐甲氧西林的细菌。氨苄青霉素也是青霉素衍生物。其开发为扩大青霉素可治疗的感染的范围,并如今在很大程度上取代了青霉素。在治疗包括呼吸道和泌尿道感染全范围感染中,该药物往往是第一选择。阿莫西林是另外一个广泛应用的青霉素衍生物。如同氨苄青霉素,该药物具有广谱活性。庆大霉素与链霉素(于1943年发现的抗结核药物)一样,属于相同的抗生素家族。该药物因为对耳朵和肾脏有严重的毒副作用,通常保留用于治疗严重感染。
最近,药物实验室开发了一种叫做喹诺酮类药物的抗生素家族,也称为氟喹诺酮类药物。除了对广范围的细菌有效之外,该类抗生素口服便可以在血液中达到高浓度。这意味着更多曾经需要住院治疗的感染现在可以在家治疗。氟喹诺酮类药物仅用于严重疾病的病人和/或需要长期使用抗生素情况(几周或几个月)的病人。
除了这些第二代化合物的发展,不断涌现的抗性问题仍然是个问题。典型的是使用后的药物抗性,尤其是药物的广泛使用或误用,最终导致该药物在治疗人类疾病中的有效性丧失。抗微生物药物的持续使用增加了选择性压力,这些选择性压力有利于耐药菌株的出现,倍增,以及传播。其原因是抗微生物药物的不合理使用和不加控制的使用,包括处方用药过量,亚适量给药,治疗时间不足,导致药物的选择不当的误诊,以及在家中和学校等地方使用(尤其是过量使用)抗菌家用产品。
在某些情况下,抗性迅速显现(比如,金黄色葡萄球菌(Staphylococcus aureus)对恶啉(OXALIN)的抗性仅在几年内形成),但是在其他情况下,可能需要更长时间才出现(比如,屎肠球菌(Enterococcus faecium)对万古霉素的抗性经过30年才形成)。这时间帧差异的原因尚不清楚,但很可能是多因素导致。但是,细菌对抗菌药物的杀伤作用的规避能力已经明显的阻碍了其在治疗个体病人中的能力以及控制传染病大爆发的能力。例如,WHO评估每年有将近500,000耐多药结核(MDR-TB)的新例,大约在9.000.000所有类型的结核病例中占了5%。
一些耐甲氧西林金黄色葡萄球菌(MRSA)菌株尤其容易在医院传播。美国的很多医院,高于70%的从病人中分离的金黄色葡萄球菌(S.aureus)为耐甲氧西林金黄色葡萄球菌,并且这些菌株往往对除万物霉素,利奈唑胺,达托霉素和替加环素以外的所有许可类药物都有抗性。最近,美国在病人中分离出完全耐万古霉素金黄色葡萄球菌菌株,这将进一步增加治疗难度。耐甲氧西林金黄色葡萄球菌在很多医院已经高度流行,该微生物一旦被引入到医院,将很难根除。
根除问题在耐万古霉素屎肠球菌(E.faecium)菌株(VRE)中也存在,该菌株通常也对各种其他临床许可药物具有抗性。屎肠球菌中的万古霉素耐性经常是质粒介导的,并可能是多种特殊的耐受因素的结果。屎肠球菌中耐青霉素和耐糖肽的结合会引发无法有效治疗的感染。但幸运的是,多数耐万古霉素屎肠球菌引发定植而非感染。当感染发生时使用抗生素是无法治疗的。喹诺酮类药物耐性甚至在治疗期间会快速形成。
现今,一些细菌已经取得“超级细菌”的地位,比如耐甲氧西林金黄色葡萄球菌,耐万古霉素肠球菌,耐喹诺酮类肺炎链球菌。针对这些病原体仅有少量或根本没有可以用于治疗的抗生素,但是,令人吃惊的是,在过去的40年里,且均从1999年开始,仅引入了少数几类新型抗生素,包括链霉杀阳菌素组合,奎奴普丁/达福普丁(共杀素),恶唑烷酮利奈唑酮,和脂肽达托霉素。
对用来治疗细菌病原体诱发的疾病的新型抗生素的需求不断增长,尤其是由于抗菌素耐药性问题。如上所述,许多病原体都显现对用于治疗的强效抗生素的抗性。令人吃惊的是,耐药性通常不仅局限于单一药物,而是可能涉及多重药物耐药性。寻找新的和更有效的药物至今仍在继续,尤其是寻找针对谱抗生素来规避多药耐药性的机制。但是,这种探索的进程非常缓慢,因为如今制药公司获得新药许可越来越困难。此外,其中涉及的费用以及从实验室中新型抗生素的鉴定到产品商业化生产许可之间的延时非常大,这已经使许多公司完全放弃了该市场。
真菌感染
真菌感染的发生率在过去的三十年中一直增长,在某种程度上是因为免疫系统失调的病人数量的增加的结果。真菌感染是近年来医学进步的直接结果,尤其是在癌症治疗中,导致免疫抑制患者数量增加。真菌感染数量增加的一些其他原因也已经提出,其中包括肠外营养和中心静脉导管,广谱抗生素治疗,怀孕,非控制糖尿病患者,实体器官移植受体,艾滋病患者,接受细胞毒性化疗的癌症患者,烧伤或中性粒细胞减少症患者,以及胃肠道疾病。
最严重的真菌感染是伴随高死亡率的侵袭性真菌感染(IFI)(比如,血液感染)。念珠菌属(Candida)是侵袭性真菌感染最常见的致病物,其平均死亡率为30%。50%的侵袭性念珠菌感染是由白色念珠菌(Candida albicans)引起,但是非白色念珠菌引发感染的相对频率也在稳步增长,也即光滑念珠菌(Candida glabrata),近平滑念珠菌(Candidaparapsilosis),热带念珠菌(Candida tropicalis)和克柔念珠菌(Candida krusei)。曲霉(Aspergillus)属真菌是最常分离的侵袭性霉菌,其中主要种类为烟曲霉(Aspergillusfumigatus)。如同念珠菌感染,侵袭性曲霉病通常伴随危重患者,虽然依赖于特异个体感染情况考虑,但该病的死亡率更高:比如,85%或更高的为侵染性或中央神经系统疾病,以及60%的为弥散性肺病。
侵袭性真菌感染的流行和死亡率在过去的三十年中持续增长。美国数据显示,1980年有828例死亡例是由该疾病引起,该病是致死感染病中第十大主要原因。1997年,同样数据资料显示,死亡数量已经上升至2370并且已经成为终极感染中第七大最主要原因。最近数据显示,念球菌已经比大肠杆菌(Escherichia coli)和假单胞菌(Pseudomonas)更广泛流行,如今已成为美国第四大最普遍的致死感染。
念珠菌侵袭性真菌感染在医院环境中增加,并且可以预计这些感染的危险因素的增加会进一步增长。美国每年8%-10%的医院中的侵袭性真菌感染是由念珠菌引起,并且每年发生率为每100,000个人中有6-23人感染。侵袭性念珠菌病的主要问题并不仅是它的高死亡率,而是感染病人3-10天的过长的住院时间,美国每年治疗念珠菌病的预算估计大约为一亿美元。最近发表的关于葡萄牙人口的研究显示,病房真菌血症的发生率为每1,000个住院者中有2.7例,死亡率为39.3%。据另一个发表的关于欧洲侵袭性真菌感染发生率的最近研究表明,该数量仿佛与欧洲其他国家的发生率更相近,但是比美国人口中发现的发生率要低很多。另一项近期报告显示,苏格兰念珠菌血症的发生率为每年每100,000人口中有4.8例。
自二十世纪五十年代末,对威胁生命的真菌感染的治疗护理标准一直是两性霉素B。该化合物以真菌细胞膜中的固醇类为靶点并与之结合,从而产生离子通道,导致膜电位的损失并之后瓦解。尽管该类药物仍然是最广谱有效的杀真菌剂,其高毒性和需要肠胃外给药限制了该类药物的使用。
1990年代见证了两性霉素B脂质体的制备,以及三唑,氟康唑和伊曲康唑的引入。三唑通过抑制CYP-450依赖的羊毛甾醇14α-去甲基化酶,其可以干扰细胞生长,从而影响麦角固醇的合成从而发挥作用并最终导致细胞死亡。这些药物与两性霉素B相比具有明显优势,但其仍受限于制备,活性谱和/或增长的耐药性。
自2000年以来,新型抗真菌药物持续发展,以克服现有药物的局限性,比如广谱三唑类(伏立康唑和泊沙康唑),以及棘白菌素(卡泊芬净、米卡芬净、阿尼芬净)。棘白菌素抑制β-1,3-D-葡聚糖的合成,导致真菌细胞壁的不稳定、细胞裂解、以及细胞死亡。该药在体外对白色念珠菌(Candida)和曲霉菌(Aspergillus)类也具有活性,但是对大范围的其他新出现的病原真菌并不具有活性。即使在这些新药物中,仍具有如药物不良反应(尤其是伏立康唑),伴随三唑药物的药物之间相互作用,以及缺乏替代制剂(如,静脉制剂缺乏泊沙康唑,而口服制剂缺乏棘白菌素)等局限。
现今有效的抗真菌药物对白色念珠菌(Candida albicans)定植的预防性根除也是低效的。事实上,这种酵母具有生物膜生长的能力,该生物膜生长表现出对抗真菌剂的天然耐性的增加,该类抗真菌剂如唑类,多烯类和5-氟胞嘧啶。因此,念珠菌经常与内置的医疗器械相关(比如,牙种植体、导管、心脏瓣膜、血管旁路移植术、眼晶状体、人工关节、以及中枢神经系统分流器),此类器械都是可以作为生物膜的生长基质。在427例念珠菌血症患者的多中心研究中,与导管相关的念珠菌血症患者的死亡率为41%。
因此,尽管新的抗菌药物在持续发展,病房真菌感染的死亡率仍然相当高。此外,新出现的真菌病原体也越来越多,包括念珠菌属非白色念珠菌(Candida)和曲霉属非烟曲霉(Aspergillus),该类真菌通常更难诊断治疗,从而引发更高的死亡率。
本发明的发明目的在于试图解决所述问题,其目的尤其在于,例如,提供一种对人/动物病原体具有有效和广谱活性并同时低毒性的可替代的抗菌剂。
发明内容
发明人惊讶的发现,源自羽扇豆属(Lupinus)的Blad多肽(Blad polypeptide)对大量不同的对人或动物体致病的细菌和真菌生物体均显示出有效的抗菌活性。本发明还发现,该Blad多肽对动物体是无毒的,因此该多肽作为针对人和动物病原体的抗菌剂,是一种非常好的化合物,广泛应用于各个领域。
因此,本发明提供了一种含Blad或其活性变体的抗菌多肽的组合物,通过治疗或预防手段用于人或动物体的治疗方法。本发明还提供了所述组合物在被微生物感染的个体体内或体表的治疗或预防的方法中的应用。在优选实施例中,该组合物进一步包含一个药学可接受的载体或稀释剂和/或螯合剂。优选的,该组合物应用于上述方法中,其中,所述个体为免疫系统缺乏的个体或重病个体。
本发明还提供了一种包含含Blad或其活性变体的抗菌多肽的组合物的应用,用以杀死或抑制对人类或动物致病的微生物的生长,该作用位点不在人或动物体体内或体表。优选的,所述组合物用于针对人或动物病原微生物,对由人类或动物摄入或者直接置于人或动物体表或体内的物品或有需要消毒的表面进行消毒,优选地,其中所述物品为食物或医疗器件或其中所述的表面位于以下的环境中:
(a)进行健康检查,诊断或治疗的环境;
(b)制作食物或处理食物或储存食物的环境;
(c)进行个人清洗和/或个人卫生的环境;和/或
(d)具有特殊风险的人所在的环境
(i)具有获得微生物感染风险的人;和/或
(ii)具有离开医疗干预便无法清除微生物感染的风险的人。
在这些应用的优选实施例中,所述组合物还进一步包含一个螯合剂。
在优选实施例中,所述微生物体为细菌或真菌,其中优选的:
-所述细菌是以下属中的其中一种病原菌属:
假单胞菌(Pseudomonas),李斯特菌(Listeria),芽孢杆菌(Bacillus),葡萄球菌(Staphylococcus)和沙门氏菌(Salmonella);或者
-所述真菌是以下属中的其中一种病原菌属:
念珠菌(Candida),曲霉菌(Aspergillus),链格孢菌(Alternaria),镰孢菌(Fusarium),隐球菌(Cryptococcus),和毛孢子菌(Trichosporon),优选的其中所述真菌能引发侵袭性真菌感染,优选的为白色念珠菌(C.albicans),烟曲霉(A.fumigatus)或互隔交链格孢菌(Alternaria alternata)。
发明人还提供了:
-一种人或动物的治疗方法,包括向有需要的个体施用含有治疗有效剂量的抗菌多肽的组合物,该抗菌多肽包含Blad或其活性变体;
-一种预防或治疗微生物感染的方法,包括给有需要的个体施用含有治疗有效剂量的抗菌素多肽的组合物,该抗菌多肽包含Blad或其活性衍生物;以及
-一种杀死或抑制对人或动物致病的微生物生长的方法,其作用位点不在人或动物体体表或体内,所述方法包括在所述作用点施用含有治疗有效剂量的抗菌多肽的组合物,该抗菌多肽包含Blad或其活性衍生物。
附图说明
本发明将参考附图进行说明,其中:
图1,显示单核细胞增生李斯特菌(Listeria monocytogenes)和铜绿假单胞菌(Pseudomonas aeruginos)的时间-杀菌曲线;
图2,显示金黄色葡萄球菌(Staphylococcus aureus),枯草芽孢杆菌(Bacillussubtilis),铜绿假单胞菌(P.aeruginosa)和单核细胞增生李斯特菌(L.monocytogenes)的抑菌圈;
图3A,显示白色念珠菌(C.albicans)的时间-杀菌曲线;
图3B和图4,显示白色念珠菌(C.albicans)的生长曲线;
图5至图8共同显示白色念珠菌(C.albicans)、新型隐球菌(Cryptococcusneoformans)和烟曲霉(A.fumigatus)的抑菌圈;
图9显示单核细胞增生李斯特菌(L.monocytogenes)、铜绿假单胞菌(P.aeruginosa)和白色念珠菌(C.albicans)的时间-杀菌曲线;
图10显示白羽扇豆(Lupinus albus)β-球蛋白前体编码序列(SEQ ID NO:1);以及
图11显示对应于Blad的β-球蛋白前体的内部片段的编码序列,(SEQ ID NO:3)。
具体实施方式
Blad
Blad("banda de Lupinus albus doce"-band from sweet L.albus,名称源自甜白花羽扇豆)是以β-球蛋白的稳定的中间的分解产物命名的,是羽扇豆属(Lupinus)的种子中主要的储存蛋白。Blad为一个20kD的多肽,由173个氨基酸残基组成,并由羽扇豆中的β-球蛋白前体的编码基因(1791个核苷酸,GenBank中储存的收录编号为AAS97865)的内部片段(519个核苷酸,GenBank中储存的收录编号为ABB13526)所编码。当编码Blad末端序列的引物用于扩增羽扇豆DNA基因组序列时,可以得到一个大约620bp的产物,表明在编码Blad的基因片段中有一个内含子存在。天然形成的Blad是210kD的低聚糖的主要成分,该低聚糖在开始发芽之后的4-12天,特异的聚集于羽扇豆的子叶中(随后β-羽扇豆球蛋白发生密集的限制性蛋白水解)。同时,所述低聚物被糖基化,天然形成的Blad是非糖基化的。含Blad的寡聚糖由多个多肽组成,其中主要的几个分子量分别为14、17、20、32、36、48和50kD。该20kD的多肽Blad,是至今为止低聚物中最丰富的多肽,并且可能是唯一一个具有凝集素活性的多肽。天然形成的Blad在8天龄植物子叶总蛋白中占大约80%。
图10显示所述白花羽扇豆β-球蛋白前体的编码序列(SEQ ID NO:1)。β-球蛋白母亚基编码序列位于70-1668位残基。编码的533氨基酸残基β-球蛋白母亚基(SEQ ID NO:2)为:
MGKMRVRFPTLVLVLGIVFLMAVSIGIAYGEKDVLKSHERPEEREQEEWQPRRQRPQSRREEREQEQEQGSPSYPRRQSGYERRQYHERSEQREEREQEQQQGSPSYSRRQRNPYHFSSQRFQTLYKNRNGKIRVLERFDQRTNRLENLQNYRIVEFQSKPNLILPKHSDADYVLVVLNGRATIIVNPDRRQAYNLEYGDALRIPAGSSYILNPDDNQKLRWKLAIPINNPGYFYDFYPSSKDQQSYFSGFSRNTLEAFNTRYEEIQRIILGNEDEQEYEEQRRGQEQSDQDEGVIVIVSKKQIQKLTKHAQSSSGKDKPSDSGPFNLRSNEPIYSNKYGNFYEIPDRNPQVQDLNISLTYIKINEGALLLPHYNSKAIYWWDEGEGNYELVGIRDQQRQQDEQEEKEEEVIRYSARLSEGDIFVIPAGYPISINASSNLRLLGFGINADENQRNFLAGSKDNVIRQLDRAVNELTFPGSAEDIERLIKNQQQSYFANGQPQQQQQQQSEKEGRRGRRGSSLPF
图11显示了对应Blad的β-球蛋白前体内部片段的编码序列(SEQ ID NO:3)。该Blad多肽(SEQ ID NO:4)为:
RRQRNPYHFSSQRFQTLYKNRNGKIRVLERFDQRTNRLENLQNYRIVEFQSKPNTLILPKHSDADYVLVVLNGRATIIVNPDRRQAYNLEYGDALRIPAGSSYILNPDDNQKLRWKLAIPINNPGYFYDFYPSSKDQQSYFSGFSRNTLEAFNTRYEEIQRIILGNED
本发明涉及一种包含含有Blad或其活性变体的抗菌多肽的组合物。因此,其涉及一种含抗菌多肽的组合物,该抗菌多肽含SEQ ID NO:4的多肽序列或其活性变体。在其中可选的具体实施例中,该组合物主要由含blad或其活性变体的抗菌多肽组成,和/或所述抗菌多肽主要由blad或其活性变体组成。在进一步的具体实施例中,所述含(或主要包含)blad或其活性变体的抗菌多肽可能以单独的方式使用。
Blad的活性变体是指保持了作为抗菌剂的能力(即具有抗菌活性-参照以下关于该活性水平和如何测量的说明)的Blad变体。“blad的活性变体”包括在其范围内的一个SEQID NO:4片段。在优选的具体实施例中,SEQ ID NO:4片段为选自为SEQ ID NO:4序列长度的至少10%,优选的为至少其长度的20%,优选的为至少其长度的30%,优选的为至少其长度的40%,优选的为至少其长度的50%,优选的为至少其长度的60%,优选的为至少其长度的70%,优选的为至少其长度的80%,优选的为至少其长度的90%,以及最优选的为至少SEQID NO:4序列长度的95%。Blad或其变体通常具有至少10个氨基酸残基的长度,如至少20个、25个、30个、40个、50个、60个、80个、100个、120个、140个、160个或173个氨基酸残基的长度。
“Blad的活性变体”还包括在其范围内的一个与SEQ ID NO:4同源的多肽序列,比如至少40%相同,优选的至少60%相同,优选的至少70%相同,优选的至少80%相同,优选的至少85%相同,优选的至少90%相同,优选的至少95%相同,优选的至少97%相同,以及最优选的至少99%相同,例如,超过全序列或超过至少20个连续氨基酸残基区域,优选的超过至少30个连续氨基酸残基区域,优选的超过至少40个连续氨基酸残基区域,优选的超过至少50个连续氨基酸残基区域,优选的超过至少60个连续氨基酸残基区域,优选的超过至少80个连续氨基酸残基区域,优选的超过至少100个连续氨基酸残基区域,优选的超过至少120个连续氨基酸残基区域,优选的超过至少140个连续氨基酸残基区域,以及最优选的超过至少160或更多的连续氨基酸残基的区域。测量蛋白同源性的方法是本领域公知常识,而且在本文内容中本领域技术人员可以理解同源性是基于相同氨基酸而计算的(有时也称为“硬同源”)。
具有同源活性的Blad变体典型的是通过取代,插入或缺失从而与SEQ ID NO:4多肽序列区别开来的,例如,通过1、2、3、4、5到8或更多位取代,缺失或插入的方式。该取代更多为“保守的”,也即,一个氨基酸可能被另一个相似氨基酸取代,相似氨基酸可以借由为以下组的其中一个:芳香残基(F/H/W/Y),非极性脂肪族残基(G/A/P/I/L/V),极性不带电脂肪族残基(C/S/T/M/N/Q)和极性带电脂肪族残基(D/E/K/R)。优选的亚族包括:G/A/P;I/L/V;C/S/T/M;N/Q;D/E;和K/R。
一种含Blad或其活性变体的抗菌多肽(如上所述)可能由在N末端和/或C末端添加了任意数量的氨基酸的Blad或其活性变体组成,并且该抗菌多肽保持了抗菌活性(再次参照以下关于所述活性水平和如何测量的说明)。优选的,不超过300个氨基酸残基添加至Blad或其活性变体的一个末端或者两个末端,更优选的,不超过200个氨基酸残基添加至Blad或其活性变体的一个末端或者两个末端,更优选的,不超过150个氨基酸残基添加至Blad或其活性变体的一个末端或者两个末端,更优选的,不超过100个氨基酸残基添加至Blad或其活性变体的一个末端或者两个末端,更优选的,不超过80、60、或40个氨基酸残基添加至Blad或其活性变体的一个末端或者两个末端,最优选的,不超过20氨基酸残基添加至Blad或其活性变体的一个末端或者两个末端。
一种包括(或主要包括)Blad或其活性变体的抗菌多肽(如上所述)可以以纯化的形式(例如,从植物、动物或微生物来源中提取)和/或重组蛋白形式。重组形式的产品使得能够产生Blad的活性变体。
本领域已经公开了纯化天然形成的Blad的方法(如,Ramos et al.(1997)Planta203(1):26-34和Monteiro et al.(2010)PLoS ONE 5(1):e8542)。天然形成的Blad的一个合适的来源为一种羽扇豆属植物,如白色羽扇豆(Lupinus albus),优选的,所述为所述植物的子叶,优选的,取在发芽开始后大约4到14天收获,更优选的,取在发芽开始后大约6到12天收获(如,发芽开始后的8天收获)。本领域已经公开了获得含Blad的粗提的全蛋白提取物的方法,以及对上述提取物纯化从而获得部分纯化提取物的蛋白纯化方法,如包含Blad的低聚糖构成的Blad。
可以用聚丙烯酰胺凝胶电泳(SDS-PAGE)法和/或,优选的,采用C-18柱反相高效液相色谱法(RP-HPLC)分离Blad本身。
另一种获得含Blad的低聚糖的部分纯化提取物的方法是利用了Blad的甲壳素绑定活性。所述低聚糖与甲壳素柱以强有力的形式结合,作为甲壳素亲和色谱纯化的一部分,以0.05N HCl洗脱。所述纯化方法的实施例详细说明如下:
收获8天龄的羽扇豆植物的子叶并在含10mM CaCl2和10mM MgCl2的Milli-Q plus中加水匀浆(pH调至8.0)。匀浆通过粗棉布过滤并30,000转,4℃离心1小时。随后取沉淀物并悬浮于pH7.5的100Mm三羟甲基氨基甲烷-盐酸(Tris-HCl)缓冲液中,该缓冲液含重量体积比为10%(w/v)的NaCl,10mM EDTA和10mM EGTA,4℃搅拌1小时,并在4℃,3000转离心1小时。上清中的总球蛋白片段用硫酸铵(561g/L)沉淀,低温搅拌1小时并在4℃,3000转离心30分钟。所得的颗粒沉淀物溶解在pH 7.5,50mM的Tris-HCl缓冲液中,在用相同缓冲液平衡过的PD-10柱中脱盐并通过在相同缓冲液中预平衡了的甲壳素亲和层析柱。该柱用pH7.5,50mM Tris-HCl缓冲液冲洗,并且将该结合蛋白用0.05NHCl洗脱。该洗脱物片段立即用2MTris中和,并用SDS-PAGE收集其峰值区的洗脱物片段,冻干并分析。
甲壳素柱的制备,从Sigma公司购买粗甲壳素并做以下处理:甲壳素样品用Milli-Q plus加水充分洗涤,然后用0.05NHCl充分洗涤。然后用重量体积比为1%(w/v)的碳酸钠洗涤,之后用乙醇洗涤,直至洗到光吸收度小于0.05。将甲壳素装入移液管端部并用pH7.5,50mMTris-HCl平衡。
生产重组蛋白的方法为本领域公知常识。其在本发明中使用的方法涉及将编码含Blad或其活性变体的多肽的多核苷酸插入到合适的表达载体上,使得所述多核苷酸与一个或多个启动子(如诱导性启动子,如T7lac)以及其他目的多核苷酸或目的基因并置,将表达受体引入到合适的细胞或者组织中(比如,大肠杆菌E.Coli),在转化细胞或组织中表达该多肽,并将表达的重组多肽从细胞或组织中提取。表达载体可以包含多核苷酸额外编码的构建以辅助纯化,例如,一个末端标签可以辅助纯化:例如,用于亲和纯化的一个组氨酸残基标签。一旦该重组多肽被纯化,纯化标签可以从多肽中去除。比如,通过溶蛋白性裂解。
在一个包含含有(或主要含有)Blad或其活性变体的抗菌多肽的组合物中,所述多肽优选的为以部分纯化的形式,更优选的以纯化的形式。当在缺少一种或多种天然与之相连的多肽的环境中和/或为至少10%总蛋白的多肽代表时,所述多肽为部分纯化形式。当在一个缺少全部,或多数与之天然相连的其他多肽的环境中时,所述多肽为纯化的形式。例如,纯化的Blad是指组合物中Blad代表了至少50%的总蛋白,至少60%、至少70%、至少75%、至少80%、至少85%、至少90%、至少95%、至少97%、至少98%、至少99%的总蛋白。
在一个包含含有(或主要含有)Blad或其活性变体的抗菌多肽的组合物中,所述羽扇豆蛋白含量可能主要由含多肽的Blad-低聚糖组成,该多肽含(或主要包含)Blad或其变体。
一个含(或主要包含)Blad的抗菌多肽的组合物其也可以是包含由本领域技术人员添加了其他化合物的配方。在优选具体实施例中,所述配方为包括一个含(或主要包含)Blad的抗菌多肽和一个药学可接受的载体或稀释剂的制药配方。
目标微生物
本发明涉及Blad作为抗菌化合物的应用,即,抑制对人或动物致病的微生物的生长,或杀死该微生物。所述微生物尤其包括细菌和真菌,该病原微生物能引起人和/或动物中的传染病或任意其他健康不佳(例如,食物中毒,过敏),并可能影响并感染以下部位包括眼睛,皮肤,烧伤,伤口,上呼吸道,肺,胃肠道,泌尿生殖道,肾脏,肝脏,神经系统和/或心血管系统(比如血液)。所述病原微生物可能是天生致病的或可能机会性致病(即在健康宿主中不引发疾病,但对免疫系统欠佳的宿主致病)。该病原微生物可能通过释放对人或动物有毒的化合物,从而也导致或选择性引起健康不佳。
Blad可以作为抗菌剂针对革兰氏阳性和革兰氏阴性细菌性病原体。尤其优选的目标细菌包括假单胞菌属病原菌(Pseudomonas),如铜绿假单胞菌(P.aeruginosa),栖稻假单胞菌(Pseudomonas oryzihabitans)和变形假单胞菌(Pseudomonas plecoglossicida)(最优选的铜绿假单胞菌(P.aeruginosa),李斯特菌属病原菌(Listeria),如单核细胞增生李斯特菌(L.monocytogenes)和伊氏李斯特菌(Listeria ivanovii)(最优选的是单核细胞增生李斯特菌(L.monocytogenes)),芽孢杆菌属病原菌(Bacillus),如枯草芽孢杆菌(B.subtilis),炭疽芽孢杆菌(Bacillus anthracis)和蜡状芽孢杆菌(Bacillus cereus)(最优选枯草芽孢杆菌(B.subtilis)),葡萄球菌属病原菌(Staphylococcus),如金黄色葡萄球菌(S.aureus)(包括耐甲氧西林金黄色葡萄球菌(Methicillin-resistantStaphylococcus aureus)【MRSA】),伪中间型葡萄球菌(Staphylococcuspseudintermedius),表皮葡萄球菌(Staphylococcus epidermidis),腐生葡萄球菌(Staphylococcus saprophyticus),里昂葡萄球菌(Staphylococcus lugdunensis),施氏葡萄球菌(Staphylococcus schleiferi)和山羊葡萄球菌(Staphylococcus caprae)(最优选金黄色葡萄球菌(S.aureus)),沙门氏菌属病原菌(Salmonella),如沙门氏菌亚种(Salmonella enterica)如亚利桑那沙门菌(Salmonella arizonae),猪霍乱沙门氏菌(Salmonella choleraesuis),肠炎沙门氏菌(Salmonella enter itidis),甲型副伤寒沙门氏菌(Salmonella paratyphi A),乙型副伤寒沙门氏菌(Salmonella paratyphi B),伤寒沙门氏菌(Salmonella typhi),鼠伤寒沙门氏菌(Salmonella typhimurium),都柏林沙门氏菌(Salmonella dublin),猪伤寒沙门氏菌(Salmonella typhisuis)和勃兰登堡沙门氏菌(Salmonella brandenburg)(最优选肠炎沙门氏菌(S.enteritidis)、伤寒沙门氏菌(S.typhi),以及弯曲菌属病原菌(Campylobacter),比如空肠弯曲菌(Campylobacterjejuni)和大肠杆菌弯曲菌(Campylobacter coli)(最优选空肠弯曲菌(Campylobacterjejuni),在优选的具体实施例中,Blad用来对抗病原菌,所述病原体能引发普通炎症的和败血症的(如铜绿假单胞菌(P.aeruginosa),霍乱(如霍乱弧菌(V.cholerae),脑膜炎(如单核细胞增生李斯特菌(L.monocytogenes),乙型流感嗜血杆菌(Haemophilus influenzaetype b),脑膜炎奈瑟菌(Neisseria meningitidis),肺炎链球菌(Streptococcuspneumoniae),肺炎(如肺炎链球菌(S.pneumoniae),无乳链球菌(Streptococcusagalactiae)或金黄色葡萄球菌(S.aureus),痢疾(如鲍氏痢疾杆菌(Shigella boydii),痢疾志贺菌(Shigella dysenteriae),弗氏志贺菌(Shigella flexneri),宋内志贺菌(Shigella sonnei),链球菌性喉炎(如酿脓链球菌(Streptococcus pyogenes),肺结核(如结核分枝杆菌(Mycobacterium tuberculosis),牛型分枝杆菌(Mycobacterium bovis),结核分枝杆菌(Mycobacterium ajricanum),氏分支杆菌(Mycobacterium canetti)和田鼠分枝杆菌(Mycobacterium microti),伤寒(鼠伤寒沙门氏菌(S.typhi)或食物中毒(如以下种属中的一种病原种类:李斯特菌(Listeria),葡萄球菌(Staphylococcus)和沙门氏菌(Salmonella)。
Blad可以用作一种针对单细胞(酵母)和多细胞(丝状病原真菌,霉菌),真菌病原菌的抗菌剂。尤其优选的目标真菌包括念珠菌属(Candida)真菌病原菌,如白色念珠菌(C.albicans),光滑念珠菌(Candida glabrata),葡萄牙念珠菌(Candida lusitaneae),近平滑念珠菌(Candida parapsilosis),热带念珠菌(Candida tropicalis),克柔念珠菌(Candida krusei)和都柏林念珠菌(Candida dubliniensis),交链孢菌属病原菌(Alternaria),如链格孢菌(A.alternata)和心虫链格孢菌(Alternaria molesta),曲霉属真菌病原菌(Aspergillus),如烟曲霉(A.fumigatus),黑曲霉(Aspergillus niger),黄曲霉(Aspergillus flavus)和棒曲霉(Aspergillus clavatus),镰孢菌属真菌病原体(Fusarium),如腐皮镰刀霉(Fusarium solani),尖孢镰刀霉(Fusarium oxysporum),轮枝镰孢菌(Fusarium verticillioides),再育镰孢菌(Fusarium proliferatum),隐球菌属真菌病原菌(Cryptococcus),如新型隐球菌(Cryptococcus neoformans),罗伦隐球菌(Cryptococcus laurentii),浅白隐球菌(Cryptococcus albidus)和gattii隐球菌(Cryptococcus gattii),以及毛孢子菌属真菌病原菌(Trichosporon),如卵圆形毛孢子菌(Trichosporon ovoides),因肯毛孢子菌(Trichosporon inkin),阿萨希毛孢子菌(Trichosporon asahii),粘状毛孢子菌(Trichosporon mucoides),星状毛孢子菌(Trichosporon asteroides),和皮状丝包酵母(Trichosporon cutaneum)(全部按照白色毛孢子菌的一般命名先前考虑),以及真皮毛孢子菌(Trichosporon dermatis),Trichosporon dohaense,和Trichosporon loubieri。在优选的具体实施例中,Blad用作对抗引起侵袭性真菌感染(IFI)的病原菌,该侵袭性真菌感染通常定义为系统的,广义的以及内脏性真菌感染,(与表面的,局部的,两性的,自限性的真菌疾病相反),该感染往往是严重的和/或危及生命的。特别优选的,引发IFI的真菌包括念珠菌属病原菌(Candida),曲霉属(Aspergillus),链格孢属(Alternaria)均属于上述所定义,优选的白色念珠菌(C.albicans),烟曲霉(A.fumigatus)和交链孢菌(A.alternata),最优选的为白色念珠菌(C.albicans)和烟曲霉(A.fumigatus)。
本领域技术人员能够通过常规方法,用含(或主要含)Blad(或其活性变体)的抗菌多肽用来在任何特定情况下的抗菌剂,确定一个合适的剂量浓度。优选的,例如,Blad的浓度至少为1μg/ml,浓度至少为5μg/ml,浓度至少为10μg/ml,浓度至少为20μg/ml,浓度至少为50μg/ml,浓度至少为100μg/ml,直到浓度为500μg/ml,直到浓度为600μg/ml,直到浓度为1mg/ml,直到浓度为2.5mg/ml,直到浓度为5mg/ml,直到浓度为10mg/ml。优选的,使用Blad的浓度选自10μg/ml和5mg/ml之间,更优选的50μg/ml和2.5mg/ml之间,更优选的100μg/ml和1mg/ml之间,以及更优选的100μg/ml和600μg/ml之间(如大约250μg/ml)。本发明提供证据证明了Blad直到浓度至少为400μg/ml,对宿主无毒(参照例4和5)。
本发明惊讶的发现,将Blad与螯合剂(如EDTA)结合能产生协同抗菌作用。因此,优选的螯合剂用于改善所述含(或主要包含)Blad(或其活性变体)多肽的抗菌活性,以及该螯合剂的使用可能降低达到抗菌活性特定水平所需的抗菌多肽的浓度。螯合试剂(也称螯合剂,络合剂或多价螯合剂)可以是与金属离子结合的以形成非共价复合物以及减少离子活性的任意组合物。合适的螯合剂包括多胺羧酸盐,如EDTA(乙二胺四乙酸)和EGTA(乙二醇-双-(β-氨基乙醚)-N,N,N’,N’-四乙酸)。优选的,螯合剂为EDTA,优选的EDTA浓度至少为10μg/ml,至少为50μg/ml,至少为100μg/ml,至少为500μg/ml,直到浓度为1mg/ml,直到浓度为5mg/ml,直到浓度为10mg/ml,直到浓度为20mg/ml。优选的,EDTA的浓度在0.1mg/ml和1mg/ml之间。
实验结果
所述含(或主要包含)Blad(或其活性变体)的抗菌多肽可用于抑制人或动物病原微生物的生长(这意味着其具有抑菌活性)或者用于杀死该微生物(意味着其具有杀菌剂活性)。本领域技术人员能够确定一个合适的剂量和/或浓度从而实现生长抑制或杀死该微生物的特定的需要。
优选的,当作为抑菌剂使用时,与相同条件下但无抗菌多肽时相比,所述抗菌多肽降低了10%的生长率,更优选的降低了50%的生长率,更优选的降低了75%的生长率,更优选的降低了90%的生长率,更优选的降低了95%的生长率,更优选的降低了98%的生长率,更优选的降低了99%的生长率,以及更优选的降低了99.9%的生长率。最优选的,抗菌多肽能防止任何微生物的生长。
优选的,当用作杀菌剂时,与相同条件下无抗菌多肽时相比,该抗菌多肽能杀死微生物总数的10%,更优选的,能杀死微生物总数的50%,更优选的,能杀死微生物总数的75%,更优选的,能杀死微生物总数的90%,更优选的,能杀死微生物总数的95%,更优选的,能杀死微生物总数的98%,更优选的,能杀死微生物总数的99%,以及更优选的,能杀死微生物总数的99.9%,最优选的,抗菌多肽杀死所有的微生物。
当用于预防或治疗人或生物体体内或体表的感染,所述抗菌多肽优选的使用治疗有效剂量,也就是说,该剂量水平是指能够杀死和/或抑制微生物生长,能达到预防感染或消除感染的临床可检测水平。优选的,所述抗菌多肽的治疗有效剂量对人或动物个体是无毒的。也即,治疗有效剂量的抗菌多肽在作为含抗菌多肽的组合物的一部分给药时,是治疗有效的。
本发明惊讶的发现,在相似的浓度(质量浓度)下,Blad对白色念珠菌和烟曲霉(在杀真菌和抑真菌活性方面)与两性霉素B的效力大致相当,且比氟康唑更为有效。这是一个惊人的结果,使得(i)与相对更小的两性霉素B和氟康唑有机分子相比,Blad有更大的分子质量,以及(ii)Blad对人类和其他动物是无毒和可食用的。
医学应用和方法
本发明提供了一种包含含有Blad或其活性变体的抗菌多肽的组合物,通过治疗或预防手段用于人或动物体的治疗方法。为此,本发明还提供了人或动物的治疗方法,其中包括给有需要的个体施用含治疗有效剂量抗菌多肽的组合物,其中所述抗菌多肽含Blad或其活性变体。
本发明还提供了一种含抗菌多肽的组合物在人体或动物体体内或体表的预防或治疗微生物感染的方法中的应用。其中所述抗菌多肽含Blad或其活性变体。为此,本发明还提供了:
-一种预防或治疗微生物感染的方法,其中包括对有需要的个体施用含治疗有效剂量抗菌多肽的组合物,其中所述抗菌多肽含Blad或其活性变体,及
-一种含抗菌多肽的组合物在制备用于人体或动物体体内或体表的预防或治疗微生物感染的药物中的应用,其中所述抗菌多肽含Blad或其活性变体。
所述组合物可以以注射(如真皮内注射,皮下注射,肌肉注射,静脉注射,骨内注射,以及腹腔注射),真皮内颗粒输送,吸入,局部施用,口服或粘膜施用(如鼻,舌下,阴道或直肠)的方式给药。
优选的,所述组合物包括一个药学可接受载体或稀释剂。这种药学组合物能以常规药学方法制备。本领域技术人员可以通过利用标准药学配方化学物和方法完成。例如,含Blad(或其活性变体)的抗菌多肽可以与一种或多种药学可接受载体或稀释剂结合从而制备液体药剂。其中也可以包含辅助物质,如湿润剂及或乳化剂,pH缓冲物质等。
所述载体,稀释剂和辅助物质为一般药学制剂,其给药无异常毒性,以及对接受该组合物的个体本身不会引起免疫应答。药学可接受载体包括但不仅限于,液体如水,盐水,聚乙二醇,透明质酸,甘油和乙醇。也可以包括药学可接受的盐,比如,无机酸盐如盐酸盐,溴酸盐,磷酸盐,硫酸盐等;以及如乙酸盐,丙酸盐,丙二酸盐,苯甲酸盐等有机酸盐。优选的但不必需的,该制备包含药学可接受的载体作为稳定剂,尤其对含有多肽(如Blad)的组合物特别有利。也可以作为多肽的稳定剂的合适的载体的例子包括,但不仅限于,药物等级的葡萄糖,蔗糖,乳糖,海藻糖,甘露醇,山梨醇,肌醇,葡聚糖等。其他适合的载体包括但也不仅限于,淀粉,纤维素,磷酸钠盐或钙盐,柠檬酸,酒石酸,甘氨酸,高分子量的聚乙二醇(PEG),和以上物质的组合。
一经制备,所述组合物可以以现有的各种途径和方法体内给个体给药。例如,液体药剂能作为可注射溶液,悬浮液或乳剂并通过胃肠外,皮下,皮肤,肌肉,静脉,骨内或腹腔注射,以常规针头和注射器或使用液体喷射注射系统,给个体给药。液体药剂也可以在眼睛,皮肤,头发或粘膜组织(例如,鼻,舌下,阴道或直肠)部位局部给药,或作为精细喷雾适用于呼吸道或肺部给药。其他给药方法包括,口服,栓剂,以及主动或被动透皮给药技术。在优选的具体实施例中,该抗菌多肽以化合物的形式制备,适合作为外用洗液,护手霜,滴眼液,洗发水或护发素。
需要该抗菌多肽的个体可以是任何人或动物个体。在优选的具体实施例中,该抗菌多肽可用于预防具有获得微生物感染的特定风险的个体的感染和/或用于治疗具有离开医疗干预便无法清除微生物感染的特定风险的个体的感染,例如年轻人,(如小于16岁的个体,如小于5岁的个体,小于3岁的个体,小于2岁的个体,小于6个月的个体,或小于1个月的个体),老年人(如大于70岁的个体,如大于80岁或大于90岁的个体),免疫系统较弱的个体(如有原发性免疫缺陷的个体,有获得性免疫缺陷的个体如艾滋病患者,和因为化疗或免疫抑制药物导致的免疫系统抑制的个体),病危个体,或者可能特定的高度暴漏于微生物病原菌的个体(如医疗专业人员)。
其他的抗菌剂的应用和方法
本发明还提供了一种包含抗菌多肽的组合物在用来杀死或抑制对人或动物致病的微生物生长中的应用,其中,所述抗菌多肽含Blad或其活性变体,所述组合物的作用位点不在人或动物体体内或体表。为此,本发明还涉及一种杀死或抑制对人类或动物致病的微生物生长的方法,其中,所述组合物的作用位点不在人或动物体体内或体表,所述方法包括在所述作用位点,施用含有效剂量的含Blad或其活性变体的抗菌多肽的组合物的给药方法。所述有效剂量是能够抑制微生物生长和/或杀死微生物的,能达到预防或消除微生物定殖的可检测的剂量水平。优选的,所述抗菌多肽的有效剂量是对人或动物个体无毒的。其目的是,所述抗菌多肽的有效剂量当作为含抗菌多肽的组合物的一部分进行给药的时候,是有效的。
该类具体实施例目的在于说明,所述抗菌多肽可以用做消毒剂以预防物品上微生物病原体的生长和/或杀死物品上微生物病原体,所述物品为可以被人或动物摄入,或直接放置于人或动物体体表或体内的,或有需要消毒的物体表面(如可能直接或间接与人或动物接触的表面),以致减少了如下所述的风险:
(i)人或动物被所述微生物病原体感染的风险;或
(ii)人或动物与微生物病原体释放的毒素接触的风险。
在优选的具体实施例中,所述抗菌多肽用在食品之中或之上,来预防该食品之上或其中人/动物微生物病原体的生长,或杀死已经存在于食品之上或之中的人/动物微生物病原体。以这种方式抗菌多肽能用来减少由于摄取该食品而导致的人或动物被微生物病原体感染的风险,或减少摄取该食品导致的人或动物摄入微生物病原体释放的毒素的风险。在这些具体实施例中,特别优选的,所述微生物病原体能够导致食物中毒(如直接或通过释放的毒素)。通过食品是指任何因为营养或令人愉悦的消费的液体或固体物质。所述含抗菌多肽的组合物例如能在食品制造过程中与其他食品成分混合或能应用于食品表面(如作为液体薄膜或喷雾)。尤其是,具体实施例中考虑的食品包括,水,软饮料如果汁,含酒精饮料,生肉,煮熟的家禽肉,蛋,牛奶,奶油,冰激凌,奶酪,生蔬菜和水果,加工食品(尤其与单核细胞增生李斯特菌(L.monocytogenes),霍乱弧菌(V.cholerae),病原葡萄球菌(Staphylococcus),病原沙门氏菌(Salmonella)和病原弯曲菌(Campylobacter)种类相关的加工食品),以及坚果和含淀粉的食物如面包,大米以及马铃薯(尤其是与致病性曲霉菌(Aspergillus)种类相关的)。
在另一个优选的具体实施例中,所述抗菌多肽用在医疗设备或仪器之中或之上,所述设备为放置在身体之内或身体之上进行诊断,治疗或手术功能的任意设备,如人工机体组织,心脏起搏器,导管,支架,阀门,温度计,注射器,皮下注射针头,监控设备,呼吸机,心脏电击器,心肺机,心电波室(EEG室)和脑电波室(ECG室),超声设备,钻头,锯,刀,解剖刀,舌簧片,剪刀,夹子和针等。所述抗菌多肽可以以上述方式用来预防在医疗过程中与设备或仪器接触的身体感染。
在另一个优选的具体实施例中,所述抗菌多肽用在有需要的表面(如可能直接或间接接触人类或动物的表面)。可以使用抗菌多肽的表面为位于以下的环境中:
(a)进行健康检查,诊断或治疗的环境;
(b)制造食物或处理食物或储存食物的环境;
(c)进行个人清洗和/或个人卫生的环境;和/或
(d)具有特殊风险的人所在的环境
(i)具有受到微生物感染风险的人;和/或
(ii)具有离开医疗干预便无法清除微生物感染的风险的人(具有该风险的个人在上文已有说明)。
该表面包括任何工业食品厂内涉及的表面和食品超市的货架/工作台的表面。
该可以使用抗菌多肽的表面可以是建筑物的地板或墙壁(如其一个房间)或所述房间或建筑物内的物体表面。
可设想的特别的建筑包括,医院和其他医疗建筑,学校和其他儿童护理中心,老年护理大厦,餐厅和其他餐馆,食品制造地,处理地和/或储存地(如市场,食品商店,超市,和食品工业工厂),以及私人住宅。可设想的特别房间包括,医疗环境中所有房间,尤其是手术室,事故和紧急部门,重症监护病房,以及厨房,卫生间,厕所,餐馆和食品制造/处理大厅。
实施例
在以下的例子中,BLAD是指天然形成的含Blad的低聚糖,其包含20kD的Blad多肽,按“per Ramos et al.(1997)Planta 203(1):26-34”中的方法纯化,参照该文献中材料和方法部分的“植物材料和生长条件”以及“蛋白纯化”的内容。
定义:
MIC-最小抑制浓度:抑制微生物可见生长的抗菌剂的最低浓度
MFC/MBC-最低杀真菌浓度/最低杀细菌浓度(或最小致死浓度):在标准化条件下24小时后,杀死99.9%初始接种菌数所需的最低杀菌剂浓度。
时间-杀菌曲线-在控制条件下测定一种或多种抗菌剂在不同时间下杀死的隔离体即为杀菌分析方法。这是一种基于液体培养基的方法,固定菌落的杀死率通过测定一定时间间隔的对照样品(有机体,无药物)和含杀菌剂的试管或烧瓶,并将每个样品涂在琼脂平板上测定存活菌落数来测定(cfu/ml)。
实施例1 Blad的杀菌活性
不同种类的细菌的BLAD的MIC和MBC(使用Mueller-Hinton培养基)
(A)单核细胞增生李斯特菌的BLAD时间-杀菌曲线和(B)铜绿假单胞菌的BLAD杀菌曲线:参照图1
针对单核细胞增生李斯特菌和铜绿假单胞菌,BLAD在浓度为100μg/ml时具有抑菌作用,浓度为250μg/ml时具有杀菌作用。
(A)金黄色葡萄球菌,(B)枯草芽孢杆菌,(C)铜绿假单胞菌,和(D)单核细胞增生李斯特菌的BLAD抑菌圈:参照图2
随处理盘中BLAD的量的增加,PCA所有检测的所有种类微生物的生长抑制也增加,从20μg(右下处理盘)到100μg(左下处理盘)和到200μg(上方处理盘)(24小时培养后的若干天均可观察到其效果)。
实施例2-BLAD的杀真菌活性
念珠菌属BLAD的MIC和MFC(RPMI培养基)
念珠菌属BLAD的MIC和MFC(使用pH 7.5的PDB培养基)
各种丝状真菌BLAD的MIC和MFC(使用RPMI培养基)
新型隐球菌(Cryptococcus neoformans)的NB-MIC在0.25-1.0μg/ml浓度下测量。
PDB培养基中白色念珠菌的BLAD的时间-杀菌曲线(A)和生长曲线(B)参照图3。
针对白色念珠菌,BLAD在浓度为10μg/ml时具有抑真菌作用,浓度为100μg/ml时具有杀真菌作用。
pH7的PDB培养基中白色念珠菌的BLAD的生长曲线:参照图4
针对白色念珠菌,BLAD和两性霉素B在浓度10μg/ml时具有抑菌作用。在浓度100μg/ml氟康唑下仅延缓生长。
针对白色念珠菌,BLAD的抑菌圈(A和B),和两性霉素B或氟康唑的抑菌圈(C):参照图5
随处理盘中BLAD的量的增加,白色念珠菌在pH7.5的马铃薯葡萄糖琼脂(PDA)培养基中的生长被抑制,从20μg(A,下方处理盘)到50μg(B,下方处理盘)和到200μg(A,上方处理盘)(培养3天)。该结果与20μg两性霉素B(C,上方处理盘)和25μg氟康唑(C,下方处理品)的抑制作用相比,该抑制抑制结果更好。
针对新型隐球菌,BLAD在PDA培养基中的抑菌圈(A),和在pH7.5的PDA培养基中的抑菌圈(B)(培养3天):参照图6
随处理盘中BLAD的量的增加,在两个培养基中培养的新生隐球菌的生长都被抑制,但在PDA培养基中抑制更明显。I-上方处理盘200μg,下方处理盘10μg;II-左上方处理盘50μg,右上方处理盘20μg,下方处理盘100μg。
针对烟曲霉的BLAD在Mueller-Hinton培养基中的抑菌圈(A)(量尺M44-A),在PDA培养基中的抑菌圈(B),和在在pH7.5的PDA培养基中的抑菌圈(C)(培养3天):参照图7.左板为显示俯视观察的培养板;右板为仰视观察的培养板。
随处理盘中BLAD的量的增加,在所有培养基中培养的烟曲霉的生长都被抑制,但在pH7.5的PDA培养基中抑制更明显。I-上方处理盘200μg,下方处理盘10μg;II-左上方处理盘50μg,右上方处理盘20μg,下方处理盘100μg。
在pH7.5的PDA培养基中,针对烟曲霉的BLAD的抑菌圈(A和B),针对烟曲霉的两性霉素B或氟康唑的抑菌圈(C)(培养6天):参照图8.
随处理盘中BLAD的量的增加,pH7.5的PDA培养基中的烟曲霉的生长被抑制,从20μg(A,下方处理盘)到50μg(B,下方处理盘)到100μg(B,上方处理盘)和到200μg(A,上方处理盘)。该结果与10mg两性霉素B(C,上方处理盘)和100mg氟康唑(C,下方处理品)的抑制作用相比,该抑制抑制结果更好。皮状丝包酵母(Trichosporon cutaneum)实验结果与之相似(数据未显示)。
实施例3-EDTA和BLAD对人病原体的杀菌活性和杀真菌活性的协同作用
对单核细胞李斯特菌(A),,对铜绿假单胞菌(B),和对白色念珠菌(C)的BLAD和/或EDTA的时间-杀菌曲线参照图9。
对单核细胞李斯特菌,BLAD在浓度为10μg/ml时,以及EDTA在浓度为0.1mg/ml时均不能抑制细菌生长,但两者结合具有抑菌作用。对铜绿假单胞菌,BLAD在浓度为50μg/ml时,或者EDTA在浓度为1mg/ml时均抑制生长(即,都具有抑菌作用),但两者结合具有杀菌作用。对白色念珠菌,BLAD在浓度为10μg/ml时,或者EDTA在浓度为0.1mg/ml时均抑制生长(即,都具有抑真菌作用),但两者结合具有杀真菌作用。
实施例4-BLAD在豚鼠中的皮肤毒性研究
里斯本理工大学兽医系高等农学院以Instituto Superior de Agronomia的名义(2006年6月18日-2006年8月1日)进行了保密研究,根据国际经济合作与发展组织(OECD)化学物质测试指南,No.402,急性皮肤毒性。该实验室按照实验室管理规范和动物福利进行实施的。
分别将单独剂量的BLAD给豚鼠给药之后,检测其急性皮肤毒性,豚鼠为皮肤毒性研究中广泛接受的合适的实验动物。将200μg/ml和400μg/ml的BLAD分别对两组实验动物中给药,每组10只。BLAD给药之后监测实验动物15天,并记录包括体重,病状和死亡数。
材料和方法:
1.材料
试验项目:5mg/ml的BLAD(淡黄色不透明液体,0-4℃)并在-80℃储存。
实验动物:白化豚鼠;品系:顿金哈德莱豚鼠(HsdPoc:DH)(来源:Harlan Iberica,巴塞罗那)。
使用动物数量:30;动物体重:400-449克;动物年龄:6周。
动物住所:所述动物单独的置于含灭菌木屑的聚乙烯箱(Lignocel)。
周围环境:
a)光照期:采用每12小时进行光照/黑暗周期循环。
b)受控的环境:平均温度19/22℃和平均湿度60%。
适应:实验开始前将所述动物在实验环境条件下保持7天。
食物:2014全球饮食,巴塞罗那Harlan Iberica提供的啮齿类动物常规饮食;水任意。
2方法
给药:试验前48小时将动物剃光,仅选取无皮肤损伤的动物用于试验。用1ml小份(浓度为200μg/ml或400μg/ml)施用于每只动物的剃光的皮肤上。
实验设计:试验的30只动物分成4组,其中两组每组10只动物,另外两组每组5只动物。其中一组10只动物的组暴露在200μg/ml的BLAD下(实验组1),另外一组10只动物的组暴露在400μg/ml的BLAD下(实验组2)。每组5只动物的两组作为对照:一组暴露在水中(1ml量)同时另一组不加任何处理但与其他组同时处理。
结果:在暴露之后,每天观察所有动物15天以记录病状或甚至死亡的任何表象。其中关于病状尤其关注暴露位点的皮肤损伤的可能症状,以及一般毒性的可能表象,如正常行为模式的变化。在暴露之前和测试期结束时分别测量动物的体重。
结果:
BLAD以以上任何浓度给药后,皮肤给药区域均没有任何物理变化、或饮水/进料、或一般行为也没有发生变化。BLAD给药后没有发生不良反应或死亡。所有组中体重增加相似(并且与该青年实验动物的正常生长的预期体重增加一致)。
结论:
BLAD在直到400μg/ml(并可能更高)的浓度时不显现皮肤毒性。
实施例5-白化大鼠中BLAD的口服实验
里斯本理工大学兽医系高等农学院以Instituto Superior de Agronomia的名义进行了保密研究,根据国际经济合作与发展组织(OECD)化学物质测试指南,No.401,急性口服毒性。该实验室按照实验室管理规范和动物福利进行实施的。
分别将单独剂量的BLAD给大鼠施用之后,分别检测其急性皮肤毒性,大鼠为口服毒性研究中广泛接受的合适的实验动物。将200μg/ml和400μg/ml的BLAD分别采用填喂法给两组实验动物给药,每组10只。给药之后监测观察实验动物15天,并在此期间记录体重,病状和死亡数。观察期之后,将动物安乐处死并进行解剖。
材料和方法-
1材料
试验项目:5mg/ml的BLAD(浅黄色不透明液体,0-4℃)并在-80℃储藏。
动物:褐家鼠;品种:Wistar Hannover大鼠,(来源:里斯本理工大学兽医系饲养室从巴塞罗那Harlan Iberica获得)
使用动物数量:30;动物的体重:250-300g;动物的年龄:10周。
动物住所:所述动物单独的放置在含灭菌木屑的聚乙烯箱子中(Lignocel)。
周围环境:
a)光周期:采用每12小时进行光照/黑暗周期循环。
b)受控的环境:平均温度19/22℃和平均湿度60%。
适应:实验开始前将所述动物在实验环境条件下保持7天。
食物:(2014全球饮食,巴塞罗那Harlan Iberica提供的啮齿类动物常规饮食;水任意。
2方法
给药:将1ml(浓度为200μg/ml或者400μg/ml)的药物以插管口服(口-食管)的方式,也即填喂法给实验动物给药,采用适合该动物品种的金属探针进行给药实验。实验动物在给药之前需18小时禁食,给药之后3小时进料。
实验设计:试验的30只动物分成4组,其中两组每组10只动物,另外两组每组5只动物。其中一组10只动物的组暴露在200μg/ml的BLAD下(实验组1),另外一组10只动物的组暴露在400μg/ml的BLAD下(实验组2)。每组5只动物的两组作为对照:一组暴露在水中(1ml量)同时另一组不加任何处理但与其他组同时处理。
结果:在暴露之后,每天观察所有动物15天以记录病状或甚至死亡的任何表象。在暴露之前和测试期结束时分别测量动物的体重。观察期之后,将动物安乐处死(通过饱和二氧化碳环境窒息致死)随后进行解剖实验。
结果:
BLAD以以上任何浓度给药后,没有任何物理变化表征、或饮水/进料、或一般行为也均没有发生变化。BLAD给药后没有发生不良反应或死亡。所有组中体重增加相似(并且与该青年实验动物的正常生长的预期体重增加一致)。此外胸腔和腹腔通过解剖实验/肉眼观察组织均未发生变化。
结论:BLAD在直到400μg/ml(并可能更高)的浓度时不显现口服毒性。
序列表
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Claims (15)
1.一种包含抗菌多肽的组合物在制备用于治疗或预防个体体内或体表微生物感染的药物中的应用,其中所述抗菌多肽为SEQ ID NO:4所示的Blad序列或其活性变体,其中所述活性变体为具有抗微生物活性并且含有与SEQ ID NO:4或具有至少100个氨基酸的SEQ IDNO:4的片段至少70%相同的序列;
所述个体为人类或动物。
2.根据权利要求1所述的应用,其中所述微生物是真菌。
3.根据权利要求1或2所述的应用,其中所述组合物进一步包括药学可接受的载体或稀释剂。
4.根据权利要求1或3所述的应用,其中所述组合物进一步包含螯合剂。
5.根据权利要求1或4所述的应用,其中所述个体有较弱的免疫系统或为病危。
6.一种包含抗菌多肽的组合物在杀死,或抑制其作用位点不在人体或动物体表或体内的对人类或动物致病性微生物的生长中的用途,其中,所述抗菌多肽为SEQ ID NO:4所示的Blad序列或其活性变体,其中所述活性变体为具有抗微生物活性并且含有与SEQ ID NO:4或具有至少100个氨基酸的SEQ ID NO:4的片段至少70%相同的序列。
7.根据权利要求6所述的用途,其中所述组合物针对人或动物致病性微生物,对由人类或动物摄入或者直接置于人或动物体表或体内的物品或有需要的表面进行消毒。
8.根据权利要求7所述的用途,其中所述物件为食物或医疗器件或仪器。
9.根据权利要求7所述的用途,其中所述表面为位于以下的环境中:
a进行健康检查,诊断或治疗的环境;
b制作食品或处理食物或储存食物的环境;
c进行个人清洗和/或个人卫生的环境;和/或
d具有特殊风险的人所在的环境
i具有获得微生物感染风险的人;和/或
ii具有离开医疗干预便无法清除微生物感染的风险的人。
10.根据权利要求6-9任意一项所述的用途,其中,所述组合物进一步包括螯合剂。
11.根据权利要求1-5任意一项所述的应用,其中当微生物是真菌时,所述真菌是以下种属的其中一种病原种类:念珠菌属、曲霉属、链格孢属、枯萎病菌属、隐球菌属和丝孢酵母属。
12.根据权利要求11任意一项所述的应用,其中所述真菌能引起侵袭性真菌感染,优选的真菌是白色念珠菌、烟曲霉菌或赤星病菌。
13.根据权利要求1任意一项所述的应用,其中所述微生物是细菌。
14.根据权利要求13任意一项所述的应用,其中所述细菌为以下种属的其中一种病原种类:假单胞菌属、李斯特菌属、芽孢杆菌属、葡萄球菌属和沙门氏菌属。
15.一种杀死或抑制对人类或动物致病性微生物生长的方法,其作用位点不在人或动物体体表或体内,所述方法包括给所述位点施用含有效剂量的抗菌多肽的组合物,其中,所述抗菌多肽为SEQ ID NO:4所示的Blad序列或其活性变体,其中所述活性变体为具有抗微生物活性并且含有与SEQ ID NO:4或具有至少100个氨基酸的SEQ ID NO:4的片段至少70%相同的序列。
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PT105332A (pt) * | 2010-10-12 | 2012-04-12 | Cev Biotecnologia Das Plantas S A | Agentes para utilização com antimicrobianos |
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