CN1138560C - 控制对抗生素耐药的革兰氏阳性细菌的方法和治疗感染的方法 - Google Patents
控制对抗生素耐药的革兰氏阳性细菌的方法和治疗感染的方法 Download PDFInfo
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Abstract
本发明涉及杀灭使人和动物致病的对抗生素耐药的病原细菌的方法。该方法使用羊毛硫抗生素(lanthocin)例如乳链菌肽作为杀菌剂。
Description
技术领域
本发明涉及预防和治疗由对抗生素耐药的病原体感染而引起的疾病的方法。这些方法使用乳链菌肽和其它含羊毛硫氨酸的细菌素(羊毛硫抗生素),以及由遗传工程或半合成化学产生的其结构变体。本发明的方法适用于抗葡萄球菌属、链球菌属和肠球菌属对抗生素耐药的菌株及其它。
背景技术
乳链菌肽(nisin)是一种由食品级微生物产生的细菌素,为抗微生物物质,属于被称为羊毛硫抗生素(lantibiotics,或lanthocin)的一组类似物质,其中还包括枯草菌素、表皮素、gallidermin、pep5、肉桂霉素、耐久霉素和血管紧张肽转化酶抑制肽。
乳链菌肽由属于蓝斯菲尔德血清学N组的乳酸乳球菌乳亚种(Lactococcuslactis subsp.lactis)产生(Mattick,A.T.R.和A,Hirsh,1947《柳叶刀》(Lancet)2,5)。乳链菌肽是一种包含34个氨基酸残基的肽,其中包含由构成羊毛硫氨酸或β-甲基羊毛硫氨酸的硫醚桥交联的5个环结构。这些硫醚由半胱氨酸的巯基与丝氨酸或苏氨酸形成的脱氢侧链缩合而成,是乳链菌肽前体肽翻译后经修饰的结果。
据报道,乳链菌肽起着阳离子表面活性剂的作用,其活性可以被阴离子去垢剂中和(Ramseier,H.R.1960 Arch.Mikrobiol,37,57),在分子水平上,乳链菌肽作用于细胞质膜而且抑制肽聚糖的生物合成(Ramseier,等.1980 Arch.Mikrobiol,127,187)。乳链菌肽抗营养期细菌的作用很可能是因为肽插入脂质双层后对细胞质膜的电压依赖性去极化作用,这可能是通过相邻乳链菌肽分子的相互作用形成一个临时性的孔或通道。乳链菌肽的分子特性及其生物合成的机制已成为目前广泛评论的主题(Jung,G.和H.G.Sahl 1991《乳链菌肽和新的羊毛硫抗生素》(Nisin and Novel Lantibiotics)ESOM Science Publishers,Leiden)。
乳链菌肽被认为只有窄谱活性而且通常只有抗革兰氏阳性菌的活性,但在与螯合剂组合时能出乎意料地抗革兰氏阴性菌并且表现出抗革兰氏阳性菌的活性增强(Blackburn等的美国专利5,135,910;5,217,950和5,260,271)。乳链菌肽目前被用作抗微生物食品防腐剂并被JEFCA及包括美国、英国和欧洲经济共同体在内的各国食品添加剂管理当局认为是安全的。
发明内容
细菌感染,尤其是在医院中获得的感染,部分由于对目前用于治疗的抗生素耐药的临床分离株的选择而更难治疗。特别是对甲氧西林耐药的金黄色葡萄球菌(MRSA)和对甲氧西林耐药的凝固酶阴性葡萄球菌(MRSE)已经变得对除糖肽类抗生素万古霉素和替考拉宁之外的大多数目前使用的抗生素具有耐药。虽然万古霉素被选作这类感染的首选药物,但它并不总是临床有效的(Karchmer,A.W.1991《内科纪事》(Annals of Internal Medicine)115:739)。肠球菌感染一直很难治疗,部分是因为它们对许多抗菌药具有固有的耐药性,部分是因为它们对于通常能够杀灭其它菌种的药物所具有的耐受性(难于杀灭)(Murray,B.E.1990《临床微生物学评论》(Clin.Microbio.Rev.)3:46)。目前,肠球菌已获得了对万古霉素的耐药性,而且由肠球菌属耐万古霉素分离株引起的感染正以惊人的速度增加,尤其是在重症监护病房中(Emori,T.G.和R.P.Gaynes 1993《临床微生物学评论》6:428)。肠球菌和葡萄球菌之间可以进行遗传信息的接合转移,在实验室中已经出现了对万古霉素耐药性的转移(Noble,W.C.等,1992,FEMSMicrobil,Lett.72:1995);所以,在医院内获得的感染中出现对万古霉素耐药的葡萄球菌似乎只是一个时间问题。在社会获得性感染中,在链球菌中出现耐药性是担心的一个原因,特别是在肺炎球菌中(Thornsberry,C.等1993《医学中的感染第10卷增刊D》:15(Infection in Medicine 10 Suppl.D):15;Stutman,H.R.1993《医学中的感染第10卷增刊D》:51)。A组链球菌(患病率及死亡率周报43:401,1994,作者不详)和葡萄球菌(引起坏死性筋膜炎和中毒性休克样综合征之类的问题)高度产毒的菌株很难治疗,经常导致病人的迅速死亡。显然,需要新的更有效而且作用更迅速的抗微生物药来对付这类感染。
虽然在原则上可以考虑将乳链菌肽用在需要抗微生物剂的某些情况中,而且该细菌素已经在动物模型的初步研究中被证明是有效的(Mattick,A.T.R和A.Hirsch,1947《柳叶刀》2:5;Bavin,E.M.等,1952《柳叶刀》1:127;Gowans,J.L.等,1952《英国药理学杂志》(Brit.J.Pharmacol.)7:438;Hiesch,A和A.T.R.Mattick 1949《柳叶刀》ii:190),但是乳链菌肽被发现不够有效以适于人或兽医治疗上的开发。阿肽加定和mersacidin是目前已被评价的较新的含羊毛硫氨酸的抗微生物肽,但被发现与目前使用的治疗药物相比对葡萄球菌和肠球菌只有中等活性(Arioli,V.等,1976《抗生素杂志》(J.Antibiotics)29:511;Somma,S.等,1977,Antimicob.Ag.Chemother;Barrett,M.S.等,1992(Diagn.Microbiol.Infect.Dis.)15:641),因而未必具有治疗价值。
但是,我们发现乳链菌肽是抗革兰氏阳性细菌病原株的强杀菌剂。具体地说,我们发现乳链菌肽对目前对多药耐药的金黄色葡萄球菌、对甲氧西林耐药的凝固酶阴性葡萄球菌、A组链球菌的某种致坏死菌株和对多药耐药的肺炎球菌具有杀菌作用。而且,我们发现乳链菌肽是对包括对万古霉素耐药的肠球菌在内的肠球菌的有效杀菌剂。由于肠球菌众所周知地对抗微生物剂具有耐性,以上结果是出乎意料的,而且有力地揭示乳链菌肽可能具有特殊的治疗价值。现已承认,广泛使用广谱抗微生物剂,尤其是低剂量口服将导致对多药耐药病原体的大量出现,所以,既然乳链菌肽是以低剂量随食物摄取的却没有出现对乳链菌肽的耐药性和对其它抗微生物剂的交叉耐药性是出人意料的。虽然在乳链菌肽作为抗微生物食品防腐剂的早期开发中没有筛选对当时各种抗生素的交叉耐药性[Hossack D JN,1988年4月6日联邦记事,vol.53,No.66.Szybalskiw,1988年4月6日,联邦记事,vol.53,No.66],但是直到现在,在乳链菌肽被任意用于食品中许多年以后,才对其对目前多药耐药的病原体的作用进行了评价。
以上发现表明不仅乳链菌肽,而且羊毛硫抗生素类抗微生物肽的其它相关成员,其中包括枯草菌素、表皮素、gallidermin、pep5、肉桂霉素、耐久霉素和血管紧张肽转化酶抑制肽,以及由遗传工程或半合成化学产生的此类分子的结构变体也应该可用于预防或治疗由对抗生素耐药的细菌在人和动物中引起的感染。
这类肽的有效药物配方包括适合活性药物胃肠外给药的单纯的水溶液,即通过静脉(i.v.)、肌内(i.m.)、皮下(s.c.)或腹腔内(i.p.)途径使活性药物在血液和组织内的水平超过其最低抑菌浓度(MIC),由此降低细菌的滴度以预防、治疗、治愈或缓解感染。据估计,羊毛硫抗生素类抗微生物药可以同时或先后与其它抗微生物药联用,以更有效地提供更广谱的治疗,尤其是在开始治疗前缺乏特异性诊断时。据估计,约每日2-200mg/kg的剂量范围能够有效地降低细菌的滴度。而且预计适合局部使用于皮肤和/或粘膜的药物配方例如水性或石油基软膏、洗剂、乳剂或凝胶剂也可用于控制对抗生素耐药的微生物。例如,某种以羊毛硫抗生素为基础的适合前鼻孔给药的局部配方,其中包含超过其MIC的活性药物浓度,因而足以降低细菌滴度,可以预计它能特别有效地控制MRSA在病人和护理人员体内的定居,由此降低获得潜在的威胁生命的对抗生素耐药的感染的危险。
具体实施方式
菌株。对甲氧西林耐药的金黄色葡萄球菌(MRSA)和表皮葡萄球菌(MRSE)是不同的欧洲医院提供的临床分离株,而高度产毒的化脓链球菌和对万古霉素耐药的粪肠球菌(Enterococcus faecalis)株则是美国的临床分离株。其它被测的MRSA、MRSE和对万古霉素耐药的屎肠球菌(Enterococcus faecium)样本都是美国的临床分离体。在各组实验中,测试了来自4个不同国家的MRSA株,来自西班牙的MRSE株,来自6个不同国家的对青霉素耐药的肺炎链球菌和来自纽约两家医院的对万古霉素耐药的肠球菌。还有其它分离株来自培养物保藏中心。
最低抑菌浓度(MIC)。主要用NCCLS(临床实验室标准国家委员会)肉汤微量稀释法来测定MIC。在使用MRSA和MRSE和对万古霉素耐药的屎肠球菌的美国分离株进行的实验中,使用的是未补充的Mueller-Hinton肉汤。在用来自不同的欧洲医院的MRSA和MRSE分离株和化脓链球菌及对万古霉素耐药的粪肠球菌美国临床分离株进行的实验中使用的是胰蛋白酶大豆肉汤。在后者中,在稀释剂中使用0.02%牛血清白蛋白(最终浓度为0.01%)来防止乳链菌肽粘着于塑料微量滴定板的孔上。
最低杀菌浓度(MBC)。在测定了MIC后,采取没有细菌生长的测试孔的样品,并进行平板培养以计数菌落。MBC定义为接触24小时内杀死最初接种物99.9%的最低浓度。
细菌培养物的裂解和快速杀菌活性。使用的培养基包括用于肺炎链球菌的’C+Y’肉汤,用于葡萄球菌的胰蛋白酶大豆肉汤和用于肠球菌的脑心浸汁肉汤。根据后文表中所述,不同种类的细菌用不同浓度的乳链菌肽在37℃培养不同的时间。测定600nm处的光密度,与接触乳链菌肽之前培养物的该值相比,以百分比的降低作为裂解率。此外,在某些实验中,基本上如在MBC中所述取样并测定活菌数。
小鼠腹腔内感染模型。将金黄色葡萄球菌NCTC8325培养在小牛肉浸汁肉汤中,每个小鼠用稀释在肉汤+10%(w/v)Difco细菌粘蛋白中的103菌落形成单位(CFU)进行腹腔内感染。以5鼠为一组,或不进行治疗,或在感染10分钟内静脉给药10mg/kg乳链菌肽(通过尾静脉,以pH5.0的0.5ml水溶液形式)。对小鼠观察48小时,以记录死亡率或不良反应。
实施例1.乳链菌肽抗目前对多药耐药的病原体的MTC和MBC测定
如表1所示,乳链菌肽对不同种葡萄球菌、肠球菌和链球菌的实验室ATCC菌株和临床分离株都表现出优良的抑菌活性(MIC),但是对革兰氏阴性菌(大肠杆菌和绿脓杆菌)作用较弱。临床分离株包括对甲氧西林耐药的金黄色葡萄球菌(MRSA)和表皮葡萄球菌(MRSE),对莫匹罗星耐药的(mup-r)金黄色葡萄球菌和MRSA,以及对万古霉素耐药的(van-r)粪肠球菌和屎肠球菌。对所有被测微生物的MBC(24小时内杀死至少99.9%细菌的浓度)都等于或在少数实验中两倍于MIC,这表明乳链菌肽对这些细菌具有高度的杀菌性。乳链菌肽对肠球菌包括对万古霉素耐药的菌株具有杀菌性是意料之外的,因为肠球菌对大多数抗菌药物的杀菌活性具有耐受性。
实施例2.乳链菌肽对于对多药耐药的病原体的杀菌活性的测定
在其它实验中,实施例1的结果得到了证实并被扩展,在这些实验中,大量葡萄球菌和肠球菌的对多药耐药的临床分离株以及对多药耐药的肺炎球菌与一定浓度的乳链菌肽接触20分钟至240分钟。在以上短时间接触后,测定两项参数:细胞存活率(测定一个实验组的)和细胞裂解率(测定两实验组的)。如表2所示,根据培养物在600nm处的浊度降低测得,大多数分离株的裂解率大于50%;其余许多菌株表现出可测出但低于50%的裂解。此外,还如表2所示测定了乳链菌肽处理的分离株的存活率。我们观察到,活菌计数的下降百分比超过了浊度的下降百分比。某些分离株的浊度显示出较小的降低,但显示出存活率的明显下降。所以,乳链菌肽对这些细菌的杀菌作用不需要细胞的裂解,而细胞裂解被认为在细菌对药物反应的后期发生。在较短的实验接触时间内,除两种分离株(两种都是与低浓度短暂接触的肺炎链球菌)之外,其余都被大量杀灭。乳链菌肽对全部肠球菌分离株的快速杀菌作用(4小时内大于或等于99%)实际上是一个值得注意的对此类微生物的作用。
实施例3.乳链菌肽对小鼠金黄色葡萄球菌腹腔感染的效果
在小鼠感染模型中测定乳链菌肽的抗感染效果。在此模型中,腹腔内感染造成未治疗动物在感染后18小时内死亡。如表3所示,5个未治疗动物都死亡,而用10mg/kg乳链菌肽静脉注射治疗的5个被感染动物都在感染后存活。该结果表明乳链菌肽在治疗感染方面具有潜在效果。
表1 乳链菌肽抗目前包括对多药耐药的病原菌的活性
菌种 | 菌株 | 分离株数 | MIC(μg/ml) | MBC(μg/ml) |
金黄色葡萄球菌表皮葡萄球菌 | ATCCMRSAMRSAmup-rMRSEMRSE | 128528 | 11-20.5-44-1624-16 | 0.5-84-164-16 |
粪肠球菌屎肠球菌 | van-rATCCvan-r | 5110 | 4-84-328-16 | 8-328-32 |
无乳链球菌化脓链球菌变异链球菌 | ATCC坏死性ATCC | 111 | 0.06<0.251 | |
大肠杆菌绿脓杆菌 | ATCCATCC | 11 | 64>128 |
表2.乳链菌肽对多药耐药的临床分离株的裂解和快速杀菌作用
菌种 | 菌株 | 乳链菌肽(μg/ml) | 时间(min) | 由A590测定的裂解率≥50%的分离株数/总数 | 存活率下降:≥99%被杀灭的分离株数/总数 |
肺炎链球菌 | pen-r | 1.01.0 | 2060 | 45/4717/18 | 16/18 |
金黄色葡萄球菌表皮葡萄球菌 | MRSAMRSE | 101010 | 120180180 | 27/3029/3310/10 | 33/3310/10 |
粪肠球菌屎肠球菌 | van-rvan-r | 1010-201010-20 | 240240240240 | 10/106/653/6012/23 | 6/623/23 |
表3在小鼠中静脉给药的乳链菌肽对金黄色葡萄球菌感染的效果
治疗 | 存活数 |
不治疗 | 0/5a |
10mg/kg乳链菌肽 | 5/5 |
未治疗的小鼠在18小时内死亡。
Claims (4)
1.乳链菌肽在制造治疗对甲氧西林和/或莫匹罗星耐药的葡萄球菌、对青霉素耐药的链球菌或对万古霉素耐药的肠球菌多药耐药菌株感染的药物中的用途。
2.根据权利要求1所述的用途,所述对甲氧西林耐药的葡萄球菌为对甲氧西林耐药的金黄色葡萄球菌和表皮葡萄球菌,所述对莫匹罗星耐药的葡萄球菌为对莫匹罗星耐药的金黄色葡萄球菌。
3.根据权利要求1所述的用途,所述对万古霉素耐药的肠球菌为对万古霉素耐药的粪肠球菌或屎肠球菌。
4.根据权利要求1所述的用途,所述对青霉素耐药的链球菌为对青霉素耐药的肺炎链球菌或坏死性化脓链球菌。
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CN108982430A (zh) * | 2017-05-31 | 2018-12-11 | 北京大学 | 标记细菌菌群样品的试剂盒、方法、带荧光标记的细菌菌群及其应用 |
CN108982430B (zh) * | 2017-05-31 | 2020-09-29 | 北京大学 | 标记细菌菌群样品的试剂盒、方法及应用 |
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NO976028D0 (no) | 1997-12-22 |
JPH11508265A (ja) | 1999-07-21 |
CZ290578B6 (cs) | 2002-08-14 |
CA2225530C (en) | 2002-08-20 |
EP0833657A1 (en) | 1998-04-08 |
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WO1997000694A1 (en) | 1997-01-09 |
SK285563B6 (sk) | 2007-03-01 |
CN1188415A (zh) | 1998-07-22 |
ATE247973T1 (de) | 2003-09-15 |
US5866539A (en) | 1999-02-02 |
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BR9609281A (pt) | 1999-06-15 |
IL122248A (en) | 2009-09-01 |
AU713050B2 (en) | 1999-11-25 |
NO976028L (no) | 1997-12-22 |
KR19990028283A (ko) | 1999-04-15 |
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