CN112739710A - 具有抗菌特性的化合物 - Google Patents
具有抗菌特性的化合物 Download PDFInfo
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- CN112739710A CN112739710A CN201980061789.2A CN201980061789A CN112739710A CN 112739710 A CN112739710 A CN 112739710A CN 201980061789 A CN201980061789 A CN 201980061789A CN 112739710 A CN112739710 A CN 112739710A
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- alkyl
- compound
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- compounds
- infection
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Abstract
Description
相关申请的交叉引用
本申请要求2018年7月19日提交的美国临时申请Nos.62/700,746及2019年1月7日提交的62/789,313的权益和优先权,通过引用,这两篇申请全文纳入本申请中。
技术领域
本发明涉及一种新型抗菌化合物及其类似物、包括所述化合物的药物组合物以及所述化合物和药物组合物的治疗用途。本发明得到美国政府支持,是美国国立卫生研究院拨款项目No.P01-AI118687完成的发明。美国政府享有本发明的某些权利。
背景技术
在易感人群中,某些革兰氏阴性菌会引起严重的并发症和感染,例如肺炎、尿路感染、伤口感染、耳朵感染、眼部感染、腹腔内感染、口腔细菌过度生长和败血症。在临床实践中,严重细菌感染的治疗可能会因抗生素耐药性而变得复杂。近年来,革兰氏阴性菌感染的人数有所上升,这些细菌对多种抗菌药物(包括氨基糖苷类、头孢菌素类及甚至碳青霉烯类等广谱抗生素)具有耐药性。这种令人震惊的趋势突出表明,需要鉴定出对革兰氏阴性菌,特别是对耐多药革兰氏阴性菌有效的新型抗菌剂。
多粘菌素是由革兰氏阳性细菌多粘芽孢杆菌产生的一类抗生素。多粘菌素,尤其是多粘菌素B和多粘菌素E(粘菌素)最早于1940年代后期被发现,曾经被用于治疗革兰氏阴性感染。但是,这些抗生素表现出副作用,例如肾毒性。因此,它们在治疗中的应用仅限于最后的治疗手段。
发明内容
本发明涉及一种新型化合物及其类似物,其表现出优异的抗菌活性,-特别是对革兰氏阴性病原体。包含所述新型化合物及其类似物的药物组合物可用于治疗或预防各种感染性疾病,包括皮肤和皮肤结构感染、呼吸道感染、败血症、菌血症和炎症性肠病(IBD)。本发明的实施例还涉及治疗或预防细菌感染。
一方面,本发明包括、基本上由或由以下式(II)表示的新型化合物
和/或其药学上可接受的盐、立体异构体(包括对映异构体)、互变异构体或水合物,以及式(II)所示化合物的类似物(以下统称为“式(II)化合物”)组成。本发明还包括包含或基本上由式(II)化合物组成的药物组合物、式(II)化合物的用途,以及采用一种或多种式(II)化合物治疗或预防细菌感染的方法。
另一方面,本发明包括、基本上由或由以下通式(I)所示新型化合物
其中:
R1、R2、R3、R4、R5和R6每个独立地选自氢、烷基、烯基、炔基、羟基、羟烷基、卤素、–CN、–O-烷基、–C(O)-烷基、–C(O)O-烷基、–C(O)OH、–C(O)NH2、–C(O)NH-烷基、–NH2、–NO2、–CF3、–NH-烷基、–N-(烷基)2、–NHC(O)-烷基和芳基,其中所述烷基、烯基、炔基和芳基任选被取代,
R7和R8每个独立地选自氢、直链或支链的C1-C5烷基、直链或支链的C2-C6烯基、直链或支链的C2-C6炔基;其中所述烷基、烯基和炔基分别任选被取代;
R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19和R20每个独立地选自氢、烷基、烯基、炔基、环烷基、环烯基、杂环烷基、杂环烯基、芳基、杂芳基、卤代烷基、羟基、羟烷基、卤素、–CN、–O-烷基、–C(O)-烷基、–C(O)O-烷基、–C(O)OH、–C(O)NH2、–C(O)NH-烷基、–NH2、–NO2、–CF3、–NH-烷基、–NHC(O)-烷基,其中所述烷基、烯基、炔基、环烷基、环烯基、杂环烷基、杂环烯基、芳基、杂芳基、卤代烷基任选被取代;
A是键或–(CH2)n–,其中n是0到10之间的整数;
X是–C(O)–、–CH2–、–C(OH)–、–C(O)O-烷基、–C((O)烷基)–,
和/或其药学上可接受的盐、立体异构体(包括对映异构体)、互变异构体或水合物,以及式(I)所示化合物的类似物(以下统称为“式(I)化合物”)组成。本发明还包括包含或基本上由式(I)化合物组成的药物组合物、式(I)化合物的用途,以及采用一种或多种式(I)化合物治疗或预防细菌感染的方法。
式(I)化合物及其前药、药学上可接受的盐、对映异构体、立体异构体、旋转异构体、互变异构体、非对映异构体和外消旋体显示出对各种革兰氏阴性菌的有利抗菌活性,并且可用于治疗或预防人类和其他动物中各种细菌引起的各种感染性疾病。
式(I)化合物包括下式(Ia):
其中:
R3、R4、R5、R6、R7和R8如上文定义,
和/或其药学上可接受的盐、立体异构体(包括对映异构体)、互变异构体或水合物,以及式(Ia)所示化合物的类似物(以下统称为“式(Ia)化合物”)。本发明还包括包含或基本上由式(Ia)化合物组成的药物组合物、式(Ia)化合物的用途,以及采用一种或多种式(Ia)化合物治疗或预防细菌感染的方法。
本发明的另一方面涉及一种治疗动物革兰氏阴性菌所引发感染的药物组合物。在不同实施例中,所述药物组合物包含治疗有效量的一种或多种式(I)、(Ia)或(II)化合物或其药学上可接受的盐,以及一种或多种选自药学上可接受的载体、表面活性剂、固体稀释剂和液体稀释剂的其他组分。式(I)、(Ia)或(II)化合物可以任选以药学上可接受的溶剂化物(例如水合物)的形式存在。
通常,如本文所述,词语“基本上”是指±10%,在一些实施例中,是指±5%。另外,在整个说明书中,“一个实例”、“一实例”、“一个实施例”或“一实施例”是指该实例描述的特定特征、结构或特性包括在本技术的至少一个实例中。因此,在整个说明书中各处出现的短语“在一个实例中”,“在一实例中”、“一个实施例”或“一实施例”不一定都指的是同一实例。此外,特定特征、结构、程序、步骤或特性可以在本技术的一个或多个实例中以任何合适的方式组合。本文提供的标题仅仅是为了方便起见,并不旨在限制或解释本技术的范围或含义。
附图说明
图1示出了254nm条件下监测得到的式(II)化合物的反相高效液相色谱(RP-HPLC)谱图,其保留时间为12.25min。
图2示出了式(II)化合物的化学结构。
图3示出了式(II)化合物对大肠杆菌的体外活性结果。式(II)化合物显示具有杀菌活性。将大肠杆菌培养至早期指数期,并用2x MIC的式(II)化合物处理。培养20小时后,将大肠杆菌培养物铺板以计数活细胞。
图4以图形方式示出了达罗布汀A(darobactin A)的生物合成基因簇和比对。
图5A示出了达罗布汀A在大肠杆菌败血症模型中的体内疗效结果。该图显示了大肠杆菌败血症小鼠的存活率。达罗布汀A能够以2.5mg/kg(ip)的剂量治愈大肠杆菌败血症小鼠:其中ATCC 25922和耐多粘菌素临床分离株AR350都可治愈,n=3/每个治疗组。感染1小时后开始治疗。1mg/kg(ip)的达罗布汀A延长了生存期,并在5h时显著降低了血液中的CFU负载。采用庆大霉素作为阳性对照,剂量为20mg/kg。
图5B示出了大肠杆菌败血症小鼠血液中每毫升菌落形成单位(CFU/mL)的结果。达罗布汀A能够以2.5mg/kg(ip)的剂量治愈大肠杆菌败血症小鼠:其中ATCC 25922和耐多粘菌素临床分离株AR350都可治愈,n=3/每个治疗组。感染1小时后开始治疗。1mg/kg(ip)的达罗布汀A延长了生存期,并在5h时显著降低了血液中的CFU负载。采用庆大霉素作为阳性对照,剂量为20mg/kg。
图5C示出了达罗布汀A在铜绿假单胞菌败血症模型中的体内疗效结果。以剂量为50mg/kg的达罗布汀A对铜绿假单胞菌P7-PA01(耐多粘菌素实验室分离株)败血症进行试验,结果表明其也可以完全治愈小鼠,每组n=3。采用庆大霉素作为阳性对照,剂量为20mg/kg。
图5D示出了达罗布汀A在大肠杆菌中性粒细胞减少大腿感染模型中的体内疗效结果。在大腿模型中,与24小时未治疗对照组相比,感染后2小时施用50mg/kg(ip)达罗布汀A,大腿中的CFU负载下降了一个对数级,而分别在感染后2小时、8小时和14小时时施用25mg/kg(ip)达罗布汀A 3次,CFU负载下降了两个对数级,包括其中有两只小鼠下降至低于检出限,每组n=4。采用庆大霉素作为阳性对照,剂量为20mg/kg。
图6示出了式(II)化合物在鼠伤寒沙门氏菌小鼠胃肠道感染中的体内疗效结果。
具体实施方式
除非另外说明,本文所述“本发明的化合物”统指式(I)、(Ia)和(II)的化合物及其药学上可接受的盐以及本文所述的具体化合物。本发明的化合物通过其化学结构和/或化学名称进行辨别。如果一种化合物通过化学结构和化学名称提及,并且化学结构和化学名称冲突,则该化合物以化学结构决定。本发明的化合物可以含有一个或多个手性中心和/或双键,因此以立体异构体的形式存在,例如双键异构体(即几何异构体)、对映异构体或非对映异构体。根据本发明,本文所述的化学结构以及因此本发明的化合物,包括所有相应化合物的对映异构体和立体异构体,即,纯形式(例如,几何纯形式、对映体纯形式或非对映体纯形式)的立体异构体及对映异构体和立体异构体的混合物。对映异构体和立体异构体混合物可以通过人们熟悉的方法拆分为它们的组分对映异构体或立体异构体,例如手性气相色谱法、手性高效液相色谱法、将化合物结晶为手性盐络合物或将化合物在手性溶剂中结晶。对映异构体和立体异构体也可以通过人们熟悉的不对称合成方法从纯形式的立体异构或对映异构中间体、试剂和催化剂获得。本发明的化合物对重要的革兰氏阴性病原体有效。这些化合物对大肠杆菌、铜绿假单胞菌、肺炎克雷伯菌、鼠伤寒沙门氏菌和宋内志贺氏菌具有良好的抗菌活性。此外,本发明的化合物对革兰氏阳性病原体没有活性,并且对革兰氏阴性肠道共生体拟杆菌属无活性。如下文详述,这种选择性在药理学上是有益的。根据其在色氨酸和赖氨酸之间包含C-C键的异常结构,本发明的化合物属于新型抗菌剂类别。实际上,在50年前发现了对抗革兰氏阴性菌的最新一类化合物。
对革兰氏阴性病原体的选择性活性非常罕见,实际上,已知只有一种化合物–即多粘菌素具有这种特性,其通过与细菌脂多糖(LPS)结合而起作用。本文所述化合物并不与LPS结合,而且重要的是,其对多粘菌素耐药突变体具有活性。多粘菌素是针对耐多药(MDR)革兰氏阴性菌的终极抗生素。
本发明的化合物具有非常低的耐药性并且没有可检测出的细胞毒性。它们可用于治疗革兰氏阴性病原体的局部和全身感染,例如皮肤和皮肤结构感染、呼吸道感染、败血症和菌血症。
本发明化合物的另一项重要应用来自它们对大肠的肠细菌致病共生菌的选择性活性。在炎症性肠病(IBD)患者中,肠杆菌科细菌,特别是大肠杆菌的大量繁殖,助长了炎症循环。普通广谱抗生素因为损害了共生微生物群,因此作用有限。本发明的化合物对革兰氏阳性菌无活性,并且对胃肠道的主要革兰氏阴性共生菌拟杆菌(Bacteroides)无活性。本发明的化合物可用于消除IBD患者中肠细菌的繁殖。肠细菌泛滥也是肠道菌群失调的普遍特征,并且将用一种或多种本发明的化合物进行治疗。
如本文所述且除非另有说明,术语“烷基”是指取代或未取代的、饱和的、直链或支链的烃链基团。烷基的实例包括但不限于C1-15直链、支链或环状烷基,例如甲基、乙基、丙基、异丙基、环丙基、2-甲基-1-丙基、2-甲基-2-丙基、2-甲基-1-丁基、3-甲基-1-丁基、2-甲基-3-丁基、2,2-二甲基-1-丙基、2-甲基-1-戊基、3-甲基-1-戊基、4-甲基-1-戊基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、2,2-二甲基-1-丁基、3,3-二甲基-1-丁基、2-乙基-1-丁基、丁基、异丁基、仲丁基、叔丁基、环丁基、戊基、异戊基、新戊基、己基和环己基以及更长的烷基,例如庚基、辛基、壬基和癸基。烷基可以是未取代烷基或被一个或两个合适的取代基取代的烷基。
如本文所述且除非另有说明,否则术语“烷氧基”是指-O-烷基,其中烷基如本文所定义。烷氧基可以是未取代烷氧基或被一个或两个合适的取代基取代的烷氧基。优选烷氧基的烷基链长度为1-5个碳原子,本文称为例如“C1-5烷氧基”。在一个实施例中,优选烷氧基的烷基链长度为1-10个碳原子,本文称为例如“C1-10烷氧基”。
如本文所述且除非另有说明,术语“烯烃”或“烯基”是指其中具有一个或多个双键的单价直链、支链或环状烃链。烯烃的双键可以是非共轭双键或与另一个不饱和基团共轭的双键。烯烃可以是未取代烯烃或被一个或两个合适的取代基取代的烯烃。合适的烯烃包括但不限于C2-8烯基,例如乙烯基、烯丙基、丁烯基、戊烯基、己烯基、丁二烯基、戊二烯基、己二烯基、2-乙基己烯基、2-丙基-2-丁烯基、4-(2-甲基-3-丁烯)-戊烯基。烯烃可以是未取代烯烃或被一个或两个合适的取代基取代的烯烃。
如本文所述且除非另有说明,术语“炔基”是指具有至少一个碳-碳三键的不饱和直链或支链烃。炔基的实例包括但不限于乙炔基、丙炔基、丁炔基、戊炔基、己炔基、甲基丙炔基、4-甲基-1-丁炔基、4-丙基-2-戊炔基和4-丁基-2-己炔基。
如本文所述且除非另有说明,术语“芳基”或“芳环”是指本领域熟悉的单环或多环共轭环结构。合适的芳基或芳环的实例包括但不限于苯基、甲苯基、蒽基、芴基、茚基、薁基和萘基。芳基可以是未取代或被一个或两个合适的取代基取代。在一个实施例中,芳基是单环,其中所述环包含6个碳原子,本文称为“C6芳基”。
“取代芳基”包括任选被一个或多个官能团取代的芳基,例如被卤素、烷基、卤代烷基(例如三氟甲基)、烷氧基、卤代烷氧基(例如二氟甲氧基)、烯基、炔基、芳基、杂芳基、芳烷基、芳氧基、芳氧基烷基、芳基烷氧基、烷氧基羰基、烷基羰基、芳基羰基、芳基烯基、氨基羰基芳基、芳硫基、芳基亚磺酰基、芳基偶氮、杂芳基烷基、杂芳基烯基、杂芳基氧基、羟基、硝基、氰基、氨基、其中氨基包括1或2个取代基的取代氨基(其任选被烷基、芳基或本文所述的任何其他取代基取代)、巯基、烷硫基、芳硫基、杂芳硫基、芳硫基烷基、烷氧基芳硫基、烷基氨基羰基、芳基氨基羰基、氨基羰基、烷基羰氧基、芳基羰氧基、烷基羰基氨基、芳基羰基氨基、芳基亚磺酰基、芳基亚磺酰基烷基、芳磺酰氨基或芳磺酰氨基羰基和/或本文所述的任何烷基取代基取代。
本文单独或作为另一基团的一部分使用的术语“杂芳基”是指包含1、2、3或4个杂原子(例如氮、氧或硫)的5-元至7-元芳环,且此类环与芳基、环烷基、杂芳基或杂环烷基环(例如苯并苯硫基、吲哚基)稠合,并包括可能的N-氧化物。“取代杂芳基”包括任选被1-4个取代基(例如以上“取代烷基”和“取代环烷基”定义中包括的取代基)取代的杂芳基。取代杂芳基还包括稠合杂芳基,其包括例如喹啉、异喹啉、吲哚、异吲哚、咔唑、吖啶、苯并咪唑、苯并呋喃、异苯并呋喃、苯并噻吩、菲咯啉、嘌呤等。
此外,本文所述术语“杂环”是指稳定的未取代或取代5-元至7-元单环体系,其可以是饱和或不饱和的,并且由碳原子和1-4个选自N、O或S的杂原子组成,其中氮和硫杂原子可任选被氧化,且氮杂原子可任选被季铵化。杂环可以连接在任何杂原子或碳原子上,导致形成稳定的结构。所述杂环基的实例包括但不限于哌啶基、哌嗪基、氧代哌嗪基、氧代哌啶基、氧代吡咯烷基、氧代氮杂卓基、氮杂卓基、吡咯基、吡咯烷基、呋喃基、噻吩基,吡唑基、吡唑烷基、咪唑基、咪唑啉基、咪唑烷基、吡啶基、吡嗪基、嘧啶基、哒嗪基、恶唑基、恶唑烷基、异恶唑基、异恶唑烷基、吗啉基、噻唑基、噻唑烷基、异噻唑基、噻二唑基、四氢吡喃基、噻吗啉基、噻吗啉基亚砜、噻吗啉基砜和恶二唑基。
本文所述术语“任选被取代”可表示例如称为烷基、芳基、杂芳基的化学单元可以是未取代或被一个或多个基团取代,所述基团包括但不限于烷基、烯基、炔基、环烷基、芳烷基、芳基、杂环、杂芳基、羟基、氨基、烷氧基、卤素、羧基、烷氧羰基、甲酰胺基、单烷基氨基亚磺酰基、二烷基氨基亚磺酰基、单烷基氨基磺酰基、二烷基氨基磺酰基、烷基磺酰氨基、羟基磺酰氧基、烷氧基磺酰氧基、烷基磺酰氧基、羟基磺酰基、烷氧基磺酰基、烷基磺酰烷基、单烷基氨基磺酰烷基、二烷基氨基磺酰烷基、单烷基氨基亚磺酰烷基、二烷基氨基亚磺酰烷基等。式I的化学单元可任选是取代烷基、烯基、炔基、环烷基、芳烷基、芳基、杂环或杂芳基。例如,任选取代烷基可包括丙基和2-氯丙基两者。此外,“任选取代”还包括其中所命名的取代基具有多个取代基而不是简单的单个取代基的实施例。例如,任选取代芳基可包括苯基和3-甲基-5-乙基-6-氯-苯基两者。
术语“环烷基”包括含有1到3个环的饱和或部分不饱和(含有1个或多个双键)环状烃基,包括单环烷基、双环烷基和三环烷基,含有形成环的总共3到20个碳,或形成环的大约3到10个碳,并且如谈到芳基时所述与1或2个芳环稠合,所述环烷基包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环癸基、环十二烷基和环己烯基。
“取代环烷基”包括任选被一个或多个取代基(例如卤素、烷基、取代烷基、烷氧基、羟基、芳基、取代芳基、芳氧基、环烷基、烷基酰胺基、烷酰基氨基、氧基、酰基、芳基羰基氨基、氨基、硝基、氰基、巯基和/或烷硫基和/或“取代烷基”定义中包含的任何取代基)取代的环烷基。
术语“环烯基”包括含有至少一个双键的非芳族单环或双环碳环。环烯基的实例包括但不限于环丙烯基、环丁烯基、环戊烯基、环己烯基、环庚烯基、环辛烯基等。
如本文所述且除非另有说明,术语“芳氧基”是指-O-芳基,其中芳基如本文所定义。芳氧基可以是未取代或被一个或两个合适的取代基取代。优选芳氧基的芳环是单环,其中所述环包含6个碳原子,本文称为“C6芳氧基”。
如本文所述和除非另有说明,术语“醚”是指通式为烷基-O-烷基、烷基-O-炔基、烷基-O-芳基、烯基-O-烯基、烯基-O-炔基、烯基-O-芳基、炔基-O-炔基、炔基-O-芳基、芳基-O-芳基的群组,其中“烷基”、“烯基”、“炔基”和“芳基”如本文所定义。
如本文所述和除非另有说明,术语“羧基”是指下式的基团:–COOH。
如本文所述和除非另有说明,术语“卤素”是指氟、氯、溴或碘。相应地,术语“卤代”和“Hal”的含义包括氟、氯、溴和碘。
如本文所述和除非另有说明,术语“取代”和“合适的取代基”是指不会使本发明化合物或用于制备本发明化合物的中间体的合成或药学用途无效的基团。取代基或合适的取代基的实例包括但不限于:C1-10烷基;C1-10烯基;C1-10炔基;C6芳基;C3-5杂芳基;C3-7环烷基;C1-10烷氧基;C6芳氧基;–CN;–OH;SH;氧基;卤素;–NO2;–CO2H;–NH2;–NHOH;–NH(C1-10烷基);–N(C1-10烷基)2;–NH(C6芳基);–NHO(C1-10烷基);–N(OC1-10烷基)2;–NH(OC6芳基);–S(C1-10烷基);–S(C6芳基);(=O);–N(C6芳基)2;–CHO;–C(O)(C1-10烷基);–C(O)(C6芳基);–C(O)O(C1-10烷基);及–C(O)O(C6芳基);–C(S)(C1-10烷基);–C(S)(C6芳基);–SO2(C1-10烷基);–SO2(C6芳基);–SO(C1-10烷基);–SO(C6芳基);及–SO3H;–C(S)O(C1-10烷基);–C(S)OC6芳基。在某些说明性实施例中,取代基可以是一个或一个以上合适的基团,例如(但不限于)-F、-Cl、-Br、-I、-OH、叠氮基、-SH、烷基、芳基、杂烷基、烷氧基、烷硫基、氨基、羟氨基、N-烷氨基、-N,N-二烷基氨基、-N,N-二甲基氨基、酰基、烷氧羰基、磺酰基、脲、-NO2和三唑基。本领域技术人员可以根据本发明化合物的稳定性以及药理和合成活性,很容易地选择合适的取代基。
本文所述短语“药学上可接受的盐”包括但不限于可以存在于本发明组合物的化合物(包括本发明的化合物)中的酸性或碱性基团的盐。本发明组合物中包括的本质上碱性的化合物能够与各种无机和有机酸形成各种盐。可用于制备此类碱性化合物的药学上可接受的酸加成盐的酸是形成无毒酸加成盐的那些酸,即含有药学上可接受的阴离子的盐,包括但不限于硫酸盐、柠檬酸盐、马来酸盐、乙酸盐、草酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、硫酸盐、硫酸氢盐、磷酸盐、磷酸氢盐、异烟酸盐、乙酸盐、乳酸盐、水杨酸盐、柠檬酸盐、柠檬酸盐、酒石酸盐、油酸盐、鞣酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、龙胆酸盐、富马酸盐、葡糖酸盐、葡糖醛酸盐、蔗糖酸盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐和双羟萘酸盐(即1,1′-亚甲基-双-(2-羟基-3-萘甲酸盐))。除上述酸外,本发明组合物中包括的包含氨基单元的化合物还可与多种氨基酸形成药学上可接受的盐。本发明组合物中包括的本质上是酸性的化合物能够与各种药学上可接受的阳离子形成碱性盐。所述盐的实例包括碱金属或碱土金属盐,尤其是钙、镁、钠、锂、锌、钾和铁盐。
本文所述术语“药学上可接受的前药”是指化合物的衍生物,其可以在生物条件下在体外或体内水解、氧化或以其他方式反应从而提供所述化合物。前药的实例包括但不限于包含可生物水解单元的化合物,例如可生物水解的酰胺、可生物水解的酯、可生物水解的氨基甲酸酯、可生物水解的碳酸酯、可生物水解的酰脲和可生物水解的磷酸酯类似物。前药的其他实例包括但不限于包含寡核苷酸、肽、类脂、脂族和芳族基团或NO、NO2、ONO和ONO2单元的化合物。前药通常可以使用众所周知的方法制备。
一方面,本文提供治疗、改善或预防受试者细菌感染的方法,包括向受试者施用治疗有效量的式(I)、式(Ia)或式(II)化合物中的至少一种化合物,或本文所述的至少一种特定化合物。所述化合物可以局部施用,例如皮下、经皮、直肠、阴道内、鼻内、支气管内、眼内或耳内施用。或者,可以全身施用,例如口服施用。在其他替代方案中,施用可以是肠胃外、静脉内、肌肉内或腹膜内施用。
本文所述词语“施用”还可以包括施用化合物的组合。因此,施用可以以向生物体施用化合物或化合物组合的形式进行,从而使生物体的循环系统将化合物或化合物组合递送至靶区域,包括但不限于一个或多个细胞、突触连接和循环。施用还可以指将化合物或化合物组合与器官、组织、区域、部位、细胞或细胞组直接接触,例如(但不限于)直接注射化合物组合。
在选择的实施例中,可以施用化合物组合,因此也可以说各种化合物彼此共同施用。本文所述“共同施用”指的是至少两种化合物中的每种化合物在生物活性或效果的各周期重叠的时间范围内施用。因此,词语“共同施用”包括各化合物顺序施用以及共延施用,其中至少一种化合物是本发明的化合物。因此,根据本发明的某些方法“施用”化合物组合包括顺序以及共延施用本发明的各种化合物。同样地,短语“化合物组合”指的是各种化合物共同施用,而短语“化合物组合”并非指各种化合物必须同时或共延施用。此外,各种化合物的施用途径不必相同。
本文所述词语“治疗”是指减慢或逆转疾病或感染的进程。治疗疾病包括治疗疾病或感染的症状和/或减轻疾病或感染的症状。词语“预防”是指减慢疾病或疾病、感染或其症状发生。预防疾病或感染可包括阻止疾病、感染或其症状的发生。
如本文所述,词语“受试者”可以是动物、脊椎动物、哺乳动物、啮齿动物(例如豚鼠、仓鼠、大鼠、小鼠)、鼠科动物(例如小鼠)、犬类(例如狗),猫科动物(例如猫)、马科动物(例如马)、灵长类动物、猿猴(例如猴子或猿)、猴子(例如绒猴、狒狒)、猿(例如大猩猩、黑猩猩、猩猩、长臂猿)或人类。
本文所述词语“剂量单位”是指物理上分散的单位,例如适合作为单位剂量提供给受试者的胶囊或片剂。每单位包含预定量的式(I)、(Ia)或(II)的化合物,所述化合物被发现或被认为会产生期望的药代动力学特征,从而实现期望的治疗效果。剂量单位由式(I)、(Ia)或(II)的化合物与至少一种药学上可接受的载体、盐、赋形剂或其组合组成。词语“剂量”是指个体一次服用或施用的活性成分的数量。
词语“治疗有效量”是指足以在受试者中产生期望生物学效应的数量。因此,化合物的治疗有效量可以是当施用于患有或易患疾病或感染的受试者时,足以治疗或预防所述疾病或感染,和/或延迟疾病或感染的发生或进程,和/或减轻疾病或感染的一种或多种症状的数量。本文所述“药学上可接受的载体”或“药学上可接受的赋形剂”是指非API(其中API是指活性药物成分)物质,例如用于配制药品的崩解剂、粘合剂、填充剂和润滑剂。它们向人类施用时通常是安全的。
词语“药学上可接受的”是指由联邦或州政府的监管机构批准或在《美国药典》或其他公认药典中列出可用于动物,尤其是人类。词语“媒介物”是指与本发明化合物一起施用的稀释剂、佐剂、赋形剂或载体。所述药物媒介物可以是液体,例如水和油,包括石油,动物、植物或合成来源的油,例如花生油、大豆油、矿物油、芝麻油等。药物媒介物可以是盐水、阿拉伯胶、明胶、淀粉糊、滑石粉、角蛋白、胶体二氧化硅、脲等。此外,可以使用辅助剂、稳定剂、增稠剂、润滑剂和着色剂。在一个实施例中,当施用于患者时,本发明化合物和药学上可接受的媒介物组合是无菌的。当本发明化合物组合静脉内施用时,水和/或油是一种媒介物。盐溶液以及葡萄糖水溶液和甘油溶液也可以用作液体媒介物,特别是用于注射液。合适的药物媒介物还包括赋形剂,例如淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽、大米、面粉、石灰石、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石粉、氯化钠、脱脂奶粉、甘油、丙烯、乙二醇、水、乙醇等。如果需要,本发明化合物的组合还可以包含少量的润湿剂或乳化剂或pH缓冲剂。
通常,本发明每种单独的化合物也可以通过任何方便的途径施用,例如口服、输注或大剂量注射,或通过上皮层或粘膜皮肤层(例如,口腔粘膜、直肠和肠粘膜等)施用,并且可以与其他生物活性剂一起施用。可以全身或局部施用。各种递送系统是已知的,例如封装在脂质体、微粒、微胶囊、胶囊等中,并且可以用于施用至少一种本发明的化合物。各种化合物的施用方法包括但不限于皮内、肌内、腹膜内、静脉内、皮下、鼻内、硬膜外、口服、舌下、鼻内、脑内、阴道内、经皮、直肠、肺或局部,尤其是耳朵、鼻子、眼睛或皮肤。优选的施用方式由从业者自行决定,并将部分取决于医疗状况。
在特定的实施例中,可能需要将组合中的一种或多种化合物局部施用于需要治疗的区域。这可以例如(但不限于)通过在手术期间局部输注,局部应用,例如结合手术后的伤口敷料,通过注射,通过导管,通过栓剂,或通过植入物来实现,所述植入物为多孔、无孔或凝胶状材料,包括膜,例如硅橡胶弹性膜(sialastic membranes)或纤维。
也可以例如通过使用吸入器或雾化器,并与雾化剂一起配制,或通过在碳氟化合物或合成的肺表面活性剂中灌注来进行肺部施用。在某些实施例中,本发明的化合物可以与传统的粘合剂和媒介物(例如甘油三酯)一起配制成栓剂。
在另一个实施例中,本发明的化合物可以在囊中,特别是脂质体中递送(参见Langer,1990,Science 249:1527-1533;Treat et al.,in Liposomes in the Therapy ofInfectious Disease and Cancer,Lopez-Berestein and Fidler(eds.),Liss,New York,pp.353-365(1989);Lopez-Berestein,ibid.,pp.317-327)。
在另一个实施例中,可将本发明方法中使用的至少一种化合物在控释系统中递送。在一个实施例中,可以采用泵(参见Langer,supra;Sefton,1987,CRCCrit.Ref.Biomed.Eng.14:201;Buchwald et al.,1980,Surgery 88:507Saudek et al.,1989,N.Engl.J.Med.321:574)。在另一个实施例中,可以使用聚合物材料(参见MedicalApplications of Controlled Release,Langer and Wise(eds.),CRC Pres.,BocaRaton,Fla.(1974);Controlled Drug Bioavailability,Drug Product Design andPerformance,Smolen and Ball(eds.),Wiley,New York(1984);Ranger and Peppas,1983,J.Macromol.Sci.Rev.Macromol.Chem.23:61;see also Levy et al.,1985,Science228:190;During et al.,1989,Ann.Neurol.25:351;Howard et al.,1989,J.Neurosurg.71:105)。在另一个实施例中,控释系统可以放置在器官(例如肝脏)附近,因此所需的施用剂量仅为全身施用剂量的一部分(参见,例如Goodson,in MedicalApplications of Controlled Release,supra,vol.2,pp.115-138(1984))。可以使用在Langer,1990,Science 249:1527-1533的综述中讨论的其他控释系统。
每种单独的化合物可以采取溶液剂、混悬剂、乳剂、片剂、丸剂、粒剂、胶囊剂、含液体胶囊剂、粉剂、缓释制剂、栓剂、乳剂、气雾剂、喷雾剂、混悬剂或其他任何适合使用的形式施用。在一个实施例中,药学上可接受的媒介物是胶囊(参见,例如,美国专利No.5,698,155)。合适的药物媒介物的其他实例在《雷明顿药学技术与实践》(21st ed.,Hendrickson,R.,et al.,Eds.,Lippincott Williams&Wilkins,Baltimore,MD(2006))中进行了说明,其通过引用而并入本发明中。
通常,当静脉内施用本发明的单个化合物时,所述化合物处于无菌等渗水性缓冲溶液中。必要时,本发明的各个化合物还可以包含增溶剂。用于静脉内施用的本发明的各种化合物可任选包括局部麻醉剂,例如利多卡因,以减轻注射部位的疼痛。
在一个实施例中,单个化合物以单位剂型一起或分开提供。无论如何,化合物可以例如以干燥的冻干粉末或无水浓缩物的形式提供在密闭容器中,例如标明活性剂含量的安瓿瓶中。当本发明的化合物或化合物组合通过输注施用时,它们可以例如用装有无菌药物级水或盐水的输液瓶分配。当通过注射施用本发明的化合物或化合物组合时,可以提供安瓿无菌注射用水或盐水,以便可以在施用之前将各成分混合。
用于口服递送的组合物可以是例如片剂、锭剂、水性或油性悬浮液、颗粒剂、粉剂、乳剂、胶囊剂、糖浆剂或酏剂的形式。口服组合物可包含一种或多种任选剂,例如甜味剂,如果糖、阿斯巴甜或糖精;调味剂,如薄荷、冬青油或樱桃;着色剂;和防腐剂,以提供药用适口制剂。用于口服的速释制剂包括片剂或胶囊剂,其包含与无毒药学上可接受的赋形剂混合的活性成分。这些赋形剂可以是例如惰性稀释剂或填充剂(例如蔗糖、山梨糖醇、糖、甘露醇、微晶纤维素、淀粉(包括马铃薯淀粉)、碳酸钙、氯化钠、乳糖、磷酸钙、硫酸钙或磷酸钠);成粒剂和崩解剂(例如,纤维素衍生物(包括微晶纤维素)、淀粉(包括马铃薯淀粉)、交联羧甲基纤维素钠、藻酸盐或藻酸);粘合剂(例如蔗糖、葡萄糖、甘露醇、山梨糖醇、阿拉伯树胶、藻酸、藻酸钠、明胶、淀粉、预胶凝淀粉、微晶纤维素、硅酸铝镁、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、聚乙烯吡咯烷酮或聚乙二醇);及润滑剂、助流剂和抗粘剂(例如硬脂酸镁、硬脂酸锌、硬脂酸、二氧化硅、氢化植物油或滑石粉)。其他药学上可接受的赋形剂可以是着色剂、调味剂、增塑剂、湿润剂、缓冲剂等,正如华盛顿特区美国药学会Arthur H.Kibbe编辑的《药物赋形剂手册》第三版中给出的赋形剂。
此外,在片剂或丸剂形式的情况下,可给组合物提供包衣以延迟在胃肠道中的崩解和吸收,从而在延长的时间内提供持续作用。包裹渗透活性驱动化合物的选择性渗透膜也适用于本发明的口服化合物。在后面的这些平台中,来自胶囊周围环境的流体被驱动化合物吸收,所述驱动化合物膨胀,从而通过孔置换试剂或试剂组合物。与立即释放制剂的飙升曲线相反的是,这些传递平台可提供基本上零级的递送曲线。也可以使用延时材料,例如单硬脂酸甘油酯或硬脂酸甘油酯。口服组合物可包括标准媒介物,例如甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、纤维素、碳酸镁等。所述媒介物优选药物级。
对于口服递送,可以将活性化合物掺入到制剂中,所述制剂包括药学上可接受的载体,例如粘合剂(例如明胶、纤维素、黄芪胶)、赋形剂(例如淀粉、乳糖)、崩解剂(例如藻酸盐、Primogel和玉米淀粉)和甜味剂或调味剂(例如葡萄糖、蔗糖、糖精、水杨酸甲酯和薄荷)。所述制剂可以以封闭的明胶胶囊或压缩片剂的形式口服递送。胶囊和片剂还可以包覆本领域已知的各种包衣,以改变胶囊和片剂的风味、口味、颜色和形状。载体可以是固体或液体,或两者均可,并且可以与作为活性化合物的本文所述的至少一种化合物一起配制,包含按重量计约0.05%至约95%的至少一种活性化合物。合适的口服制剂也可以是悬浮液、糖浆、口香糖、糯米纸囊剂、酏剂等形式。
如果需要,还可以包括用于改变特殊形式的风味、口味、颜色和形状的常规试剂。此外,为了方便不能吞咽的患者通过肠内饲管施用,可以将活性化合物溶解在可接受的亲脂性植物油媒介物中,例如橄榄油、玉米油和红花油中。
活性化合物也可以以溶液或悬浮液形式或以能够在使用前转化成溶液或悬浮液形式的冻干形式肠胃外施用。在这样的制剂中,可以使用稀释剂或药学上可接受的载体,例如无菌水和生理盐水缓冲剂。可以包括其他常规溶剂、pH缓冲剂、稳定剂、抗菌剂、表面活性剂和抗氧化剂。例如,有用的组分包括氯化钠、乙酸盐、柠檬酸盐或磷酸盐缓冲剂、甘油、右旋糖、不挥发性油、对羟基苯甲酸甲酯、聚乙二醇、丙二醇、硫酸氢钠、苄醇、抗坏血酸等。肠胃外制剂可以储存在任何常规容器中,例如小瓶和安瓿瓶中。
局部施用的途径包括鼻、颊、粘膜、直肠或阴道施用。对于局部施用,可以将活性化合物配制成洗剂、霜剂、软膏剂、粉剂,糊剂、喷雾剂、混悬剂、滴剂和气雾剂。因此,制剂中可包含一种或多种增稠剂、湿润剂和稳定剂。所述试剂的实例包括但不限于聚乙二醇、山梨糖醇、黄原胶、凡士林、蜂蜡或矿物油、羊毛脂、角鲨烯等。局部施用的一种特殊形式是通过透皮贴剂递送。制备透皮贴剂的方法例如在Brown,et al.(1988)Ann.Rev.Med.39:221-229中进行了公开,通过引用,该文献纳入本发明中。可以使用的载体和赋形剂包括凡士林、羊毛脂、聚乙二醇、醇及它们中的两种或更多种的组合。活性化合物的浓度通常为组合物的约0.1%至约80%w/w,例如约0.2%至50%。
用于持续释放活性化合物的皮下植入也可以是合适的施用途径。这需要采用外科手术,将任何合适制剂中的活性化合物植入到例如前腹壁下方的皮下空间。参见,例如Wilson et al.(1984)J.Clin.Psych.45:242-247。水凝胶可作为持续释放活性化合物的载体。水凝胶是本领域熟知的。它们通常是通过将高分子量生物相容聚合物交联成网络制成的,所述网络在水中膨胀形成凝胶状材料。优选水凝胶是可生物降解的或可生物吸收的。对本发明来说,由聚乙二醇、胶原蛋白或聚(乙醇酸-共-L-乳酸)制成的水凝胶可能是有用的。参见,例如Phillips et al.(1984)J.Pharmaceut.Sci.,73:1718-1720。
每种化合物的施用量取决于症状的性质或严重程度,可以通过标准的临床技术确定。此外,可以任选采用体外或体内测定法来帮助确定组合中每种组分的最佳剂量范围。所采用的每种成分的精确剂量还取决于施用途径和疾病或病症的严重性,并且从业者可以根据每个患者的情况确定这些剂量。然而,一般而言,每种式(I)化合物、式(Ia)化合物和式(II)化合物的口服施用的合适剂量范围通常是约0.001mg至1000mg本发明化合物/公斤体重。在本发明的具体实施例中,每种组分的口服剂量是每公斤体重0.01mg至100mg,更特别地是每公斤体重0.1mg至50mg,更特别地是每公斤体重0.5mg至20mg,甚至更特别地是每公斤体重1mg至10mg。在一个实施例中,每个式(I)化合物、式(Ia)化合物和式(II)化合物的口服剂量为至少约1、5、10、25、50、100、200、300、400或500mg/天至高达600、700、800、900、1000mg/天,持续三到十五天。式(I)化合物、式(Ia)化合物和式(II)化合物中的每一种化合物都可以每天(例如每天一次、两次、三次或四次)或更不频繁地(例如两天一次,或每周一次或两次)施用。本文所述的剂量是指所施用的个体剂量。当施用一种以上的化合物时,优选的剂量对应于所施用的本发明化合物的总量。本文所述的口服组合物可包含按重量计约10%至约95%的活性成分。
通常,单组分静脉内(i.v.)施用的合适剂量范围是每公斤体重0.001mg至1000mg、每公斤体重0.01mg至100mg、每公斤体重0.1mg至50mg及每公斤体重1mg至10mg。通常,单组分鼻内施用的合适剂量范围一般为约0.01pg/kg体重至1mg/kg体重。通常,栓剂一般为每千克体重含约0.01mg至50mg化合物,并且可包含0.5重量%至10重量%的活性成分。有效剂量可以从体外或动物模型测试系统的剂量-反应曲线中推断得出。所述动物模型和系统是本领域熟知的。
本发明还涉及药物包或试剂盒,其包括一个或多个装有实施本发明方法时施用的一种或多种化合物的容器。任选与所述容器相关联的通知可以是监管药品或生物产品生产、使用或销售的政府机构规定的形式,所述通知反映了获得了生产、使用或销售机构对人类施用的批准。在某个实施例中,所述试剂盒包含一种以上的化合物。
本文所述的化合物可用于治疗由易感或耐多药细菌、耐多粘菌素突变体、耐碳青霉烯菌、耐甲氧西林金黄色葡萄球菌、耐万古霉素肠球菌或耐多药淋病奈瑟氏菌引发的感染。
革兰氏阴性菌的实例包括但不限于大肠杆菌、铜绿假单胞菌、韧皮部杆菌、根癌土壤杆菌、卡他布兰汉菌、柠檬酸杆菌、产气肠杆菌、肺炎克雷伯菌、奇异变形杆菌、鼠伤寒沙门氏菌、脑膜炎奈瑟氏菌、粘质沙雷氏菌、宋内志贺氏菌、鲍氏志贺氏菌、淋病奈瑟氏菌、鲍曼不动杆菌、肠炎沙门氏菌、具核梭杆菌、极小韦永氏球菌、伴放线放线杆菌(Actinobacillus actinomycetemcomitans)、放线共生放线杆菌(Aggregatibacteractinomycetemcomitans)、牙龈卟啉单胞菌、幽门螺杆菌、土拉弗朗西斯菌、鼠疫耶尔森菌、霍乱弧菌、摩氏摩根菌(Morganella morganii)、迟缓爱德华菌、空肠弯曲杆菌或流感嗜血杆菌、阴沟肠杆菌及其它许多细菌。其他值得注意的革兰氏阴性菌包括蓝细菌、螺旋菌、绿色硫细菌和绿色非硫细菌。
医学上相关的革兰氏阴性球菌包括三种导致性传播疾病(淋病奈瑟氏菌)、脑膜炎(脑膜炎奈瑟氏菌),和呼吸道症状(卡他莫拉菌)的生物。
医学上相关的革兰氏阴性杆菌包括许多种。其中一些主要引起呼吸系统问题(流感嗜血杆菌,肺炎克雷伯菌、嗜肺军团菌、铜绿假单胞菌),主要引起泌尿系统问题(大肠杆菌、阴沟肠杆菌),主要引起胃肠道问题(幽门螺杆菌、肠道沙门氏菌)。
与医院感染有关的革兰氏阴性菌包括鲍曼不动杆菌,这种菌在医院机构的加护病房中引起菌血症、继发性脑膜炎和呼吸机相关性肺炎。在一个实施例中,本发明的化合物和组合物可用于治疗以下一种或多种革兰氏阴性菌的感染:大肠杆菌、肠道沙门氏菌,克雷伯菌:肺炎克雷伯菌、产酸克雷伯菌;肠杆菌:阴沟肠杆菌、产气肠杆菌、成团肠杆菌,不动杆菌:醋酸钙不动杆菌、鲍曼不动杆菌;铜绿假单胞菌、嗜麦芽寡养单胞菌、斯氏普罗威登斯菌、变形杆菌:奇异变形杆菌、普通变形杆菌。
在一个实施例中,式(I)、(Ia)或(II)的化合物或其药学上可接受的盐或包含它们的组合物可用于治疗假单胞菌感染,包括铜绿假单胞菌感染,例如皮肤和软组织感染、胃肠道感染、尿路感染、肺炎和败血症。
在一个实施例中,式(I)、(Ia)或(II)的化合物或其药学上可接受的盐或包含它们的组合物可用于治疗包括鲍曼不动杆菌感染在内的不动杆菌感染,用于治疗肺炎、尿路感染和败血症。
在一个实施例中,式(I)、(Ia)或(II)的化合物或其药学上可接受的盐或包含它们的组合物可用于治疗克雷伯氏菌感染(包括肺炎克雷伯菌感染),用于治疗肺炎、尿路感染、脑膜炎和败血症。
在一个实施例中,式(I)、(Ia)或(II)的化合物或其药学上可接受的盐或包含它们的组合物可用于治疗大肠杆菌感染(包括大肠杆菌感染),用于治疗菌血症、胆囊炎、胆管炎、尿路感染、新生儿脑膜炎和肺炎。
本发明的化合物可以通过在受控条件下使微生物菌株Photorhabdus khanii DSM3369生长来制备。所述化合物通过发酵获得并以本文所述的基本纯形式回收。特别是,本发明的化合物可以在下文所述的条件下,在合适的营养培养基的有氧发酵期间,由Photorhabdus P.khanii DSM 3369菌株产生。诸如用于产生许多抗菌物质的培养基适用于本发明化合物的产生方法。
本发明的一个实施例包括一种适合产生抗生素(例如式(II)化合物)的方法,所述方法通过Photorhabdus khanii DSM 3369的深层通气发酵进行。式(II)化合物可以通过吸收树脂从发酵液中回收,并采用各种极性的溶剂洗涤,从树脂中洗脱。可以通过色谱分离例如反相高效色谱法(RP-HPLC)进一步纯化。
能够产生本发明的一种或多种化合物的其他微生物包括突变种,与本领域已知的种相比,突变种具有有利的特性。所述细菌菌株可以通过亲本菌株的突变产生。突变的策略和方法,突变细菌菌株的筛选和分离程序,用于产生本发明突变菌株的培养基的组成是本领域已知的。
在优选的实施例中,用于产生式(II)化合物的Photorhabdus khanii DSM 3369的培养在含有易同化碳核、氮源、无机盐和其他有机成分以及一种或多种吸收剂的营养培养基中,在适当的曝气条件下并在无菌环境下混合而进行。用于产生本发明抗生素的营养培养基的组成将在实施例中进行详细描述。(本文所述词语“营养培养基”描述了合成或天然成分的混合物。通常,营养培养基包括碳源、氮源、微量元素(如无机盐)以及任选维生素或其他生长因子)。
可以使用直接获得的编码本发明化合物的野生型基因组序列变异,生物合成产生本文所述化合物的类似物。根据Photorhabdus khanii DSM 3369的基因组序列,及如图4所示,式(II)化合物达罗布汀A的线性化氨基酸序列(WNWSKSF(SEQ ID NO:1))与属于典型编码RiPP的操纵子的基因的一部分(核糖体合成和翻译后修饰肽)-型抗菌剂之间存在匹配。操纵子包含一个生物合成基因簇,所述簇(按我们在这里介绍的命名法)编码darA(编码达罗布汀A的前体肽、达罗布汀A、式(II)化合物)),darBCD(编码显然用于达罗布汀A的输出的转运蛋白),darE(形成未激活的C-C键(例如达罗布汀A的trp-lys C-C键)所需的自由基SAM酶)。前体肽中显示了达罗布汀A的7aa序列。序列比对表明在许多发光杆状菌中存在dar操纵子,其核心肽是保守的。
已经获得了对达罗布汀具有抗性的大肠杆菌突变体,并且它们映射到BamA,BamA是Bam复合物的重要组成部分,有助于折叠蛋白质并将蛋白质插入外膜。
达罗布汀A核心肽的核糖体编码显然意味着所有氨基酸均为L形式。核糖体编码使得能够通过编码前体肽的darA基因中的核苷酸取代来产生达罗布汀A的类似物。所述取代可以使用各种标准生化方法中的任何一种来实现。具有达罗布汀A编码区核苷酸的特异性和随机取代的寡核苷酸的合成将产生大量的片段。这些寡核苷酸将与编码前体肽的上游和下游序列连接,被克隆到表达载体中,并被转化成带有破坏的前体肽基因的dar操纵子的细胞。从该重组文库的克隆中分离出达罗布汀A、达罗布汀A类似物,并测试其活性。可以分离出抗菌效力增强或药理性质改善的类似物,并将其开发成药物。
技术上合适的话,可以组合各实施例,因此本发明扩展为本文提供的各实施例的所有排列/组合。本文的实施例仅用于说明目的,并非以任何方式限制本发明的范围。
示例
发酵
将Photorhabdus khanii DSM 3369接种到10ml Luria Bertani肉汤(LBB)中,并在28℃摇动(200rpm)条件下于50ml离心管中培养。将培养了1个晚上的10毫升培养物接种到2L锥形瓶中的1L胰酶大豆肉汤(TSB)中,并在28℃摇动(200rpm)条件下培养8至10天。
分离
通过离心(8,000×g,10分钟)除去细菌细胞,并回收上清液。将上清液与活化的苯乙烯-二乙烯基苯树脂(AMBERLITE XAD16N,SIGMA-ALDRICH)混合(4∶1;v/v),然后在环境温度下轻轻摇动1个晚上。通过倾析除去未结合的物质,并用六倍于树脂体积的dd-水(双蒸水)洗涤吸附在树脂上的化合物达罗布汀A(对应于式(II))。在旋转摇床上轻轻摇动30分钟,用四倍树脂体积的50%甲醇(含0.1%(v/v)甲酸)洗脱达罗布汀A。洗脱液通过旋转蒸发仪浓缩以除去有机溶剂。用0.1%(v/v)的甲酸酸化剩余的洗脱液,然后在松散的树脂本体工艺中进行阳离子交换色谱(SP Sepharose XL,GE Healthcare)分析。将活化的阳离子交换树脂加入到酸化的洗脱液中,并在4℃轻轻摇动1个晚上。倾析未结合的物质,并用含0.1%(v/v)甲酸的dd-水洗涤树脂。通过50mM醋酸铵pH 5、50mM醋酸铵pH 7和50mM醋酸铵pH8的逐步梯度洗脱抗生素活性成分。汇合抗生素活性洗脱液,冷冻干燥,然后重悬于含0.1%(v/v)甲酸的dd-水中。通过逐步pH梯度洗脱,在串联连接的四个HiTrap SP XL柱上对重悬浮液进行第二次阳离子交换色谱分析(每个柱5mL;总柱床体积为20mL)。未结合的物质用含0.1%(v/v)甲酸的dd-水洗涤,然后通过50mM醋酸铵pH 5、50mM醋酸铵pH 7和50mM醋酸铵pH8的逐步梯度洗脱。汇合抗生素活性洗脱液,冷冻干燥,然后重悬于含0.1%(v/v)甲酸的dd-水中,在C18半制备柱上进行反相高效色谱(RP-HPLC)(Agilent,C18,5μm;250x 10mm,Restek)分析,采用水+含0.1%(v/v)甲酸的溶剂A/乙腈+含0.1%(v/v)甲酸的溶剂B的线性梯度,溶剂B在14分钟内从2%B开始升到14%B,流速5mL/min,在二极管阵列检测器上开展210至400nm的紫外检测,得出达罗布汀A保留时间为12.25分钟(纯度:95%UV)。
达罗布汀A的结构
冻干后,分离出呈无定形白色粉末的达罗布汀A。
达罗布汀A的化学测试表明存在伯胺,因为它与茚三酮试剂呈阳性反应。它还对氯化铁测试呈阳性反应,表明存在苯酚。
通过直接注射浓度1μg/ml的达罗布汀A,采用THERMO SCIENTIFIC LTQ OrbitrapXL混合离子阱-轨道离子阱质谱仪获得高分辨率电喷雾电离质谱(HRESIMS),结果显示在m/z483.70874处出现[M+2H]2+峰,在m/z 966.41046处出现[M+H]+峰。同位素模式表明不存在Cl或Br。准确的质量和同位素分布与C47H55O12N11的基本通式一致。
将5mg达罗布汀A溶于500μL水+3%(v/v)氧化氘和0.25%(v/v)氘代甲酸中,采用布鲁克500MHz仪器开展一维和二维核磁共振(1D和2D NMR)分析,表明存在一种肽,并表明存在苯丙氨酸、两个丝氨酸、赖氨酸、两个色氨酸和天冬酰胺。COSY、TOCSY、NOESY和HMBC光谱可通过肽键确定不同氨基酸的连接,表明存在异常的赖氨酸-色氨酸交联。这种连接可能是由R.Schramma et al.2015先前描述的翻译后修饰引起的,涉及赖氨酸和色氨酸侧链中两个未活化碳之间的共价键。
酸水解达罗布汀A,然后用Marfey试剂衍生化,并进行LC-MS氨基酸测定实验,并通过串联质谱(MS/MS)对整个化合物的片段化模式进行分析,证实了该肽的序列表明是一种新的天然产物。
抗菌谱
通过肉汤微量稀释测定法确定达罗布汀A的最低抑菌浓度(MIC)。采用下列测试生物评估达罗布汀A的抗菌谱:铜绿假单胞菌、大肠杆菌、鲍曼不动杆菌、肺炎克雷伯菌、金黄色葡萄球菌、鼠伤寒沙门氏菌、宋内志贺氏菌、阴沟肠杆菌、脆弱拟杆菌、罗伊氏乳杆菌和粪肠球菌。
需氧条件下将测试生物接种到5mL Muller Hinton II肉汤(MHIIB)或厌氧条件下接种到脑心浸液肉汤(BHI)中,生长至细胞密度达到OD600=0.1-0.9。将细胞悬浮液稀释至OD600=0.001,然后将96μL细菌培养物添加到96孔板的4μL达罗布汀A中(最终浓度0.5至128μg/mL)中。在37℃下培养20小时后,目测确定测试生物的生长情况(表1)。
表1
达罗布汀A抗测试生物的MIC
MIC通过肉汤微量稀释测定法测定。分离出铜绿假单胞菌的自发耐多粘菌素突变体。
细胞毒性
将HepG2和FaDu细胞在75cm2组织培养瓶中的20mL最低必需培养基(MEM)+10%胎牛血清(FBS)和1%抗生素-抗真菌溶液中培养,并在37℃和5%CO2下培养5天(直到细胞达到70%融合)。除去生长培养基,并用5mL 1×磷酸盐缓冲盐水(PBS)冲洗细胞。冲洗后,除去PBS,并加入2mL含0.25%胰蛋白酶的1x EDTA溶液。将细胞在37℃和5%CO2中培养2分钟,以使细胞脱离烧瓶。向烧瓶中添加6mL培养基使胰蛋白酶失活,并通过温和移液将细胞分离,以避免结块。对细胞进行计数,并在MEM+10%FBS中稀释至2x 105细胞/mL,然后将100μl此悬浮液添加到透明、平底、组织培养处理的96孔板中。将所述孔板在37℃和5%CO2下培养1个晚上,以使细胞粘附到孔板上。
在单独的透明、圆底、未经组织培养处理的96孔板中,将4μl达罗布汀A与96μl培养基混合。从每个组织培养板上除去上清液,并将含有达罗布汀A的培养基从圆底孔板转移到组织培养板上。将细胞在达罗布汀A的存在下于37℃和5%CO2中培养3天,然后加入5μl 3mM刃天青(Alamar Blue)。将孔板在37℃、5%CO2条件下培养3小时。通过读取平板读取器上的荧光(554nm/590nm)来评估每种细胞系的活性(表2)。
表2
达罗布汀A对人类细胞系的细胞毒性
HepG2和FaDu细胞用达罗布汀A处理,并通过刃天青(Alamar blue/MABA)分析计算达罗布汀A的50%抑制浓度(IC<50)。
达罗布汀A的杀伤活性
将大肠杆菌接种到5mL Mueller Hinton II肉汤(MHIIB)中,并生长到OD600=0.1-0.9。将细胞悬浮液稀释至OD600=0.001。在96孔板中,将98μL大肠杆菌培养物用2μL达罗布汀A(16μg/mL,对应于2xMIC)处理,并在37℃下培养20小时。将大肠杆菌培养物接种到无抗生素的Luria Broth琼脂上,并计数菌落形成单位(CFU)来计数活细胞(图3)。
脂多糖(LPS)拮抗试验
达罗布汀A是分子量为966Da的大化合物。渗透到革兰氏阴性菌中的分子量极限约为500Da。因此,达罗布汀A似乎可能作用于细胞表面,与靶向脂多糖(LPS)的多粘菌素类似。为了测试这一点,在LPS存在下测试了达罗布汀A的活性。将大肠杆菌接种到5mL MHIIB中,并生长直到细胞密度达到OD600=0.1-0.9。将细胞悬浮液用2x MHIIB稀释至OD600=0.002。40μL LPS溶液(最终浓度范围为0至800μg/mL)和2μL 2xMIC抗生素溶液(最终浓度:多粘菌素:0.5μg/mL,氨苄青霉素:16μg/mL,达罗布汀A:16μg/mL)在96孔板中混合,并用无菌去离子水加至50μL。将LPS和抗生素溶液与50μL大肠杆菌细胞悬液混合,并在37℃下培养20小时。肉眼确定大肠杆菌的生长情况(表3)。
表3
LPS拮抗达罗布汀A的抗菌活性
将LPS与2xMIC抗生素一起培养,并监测对大肠杆菌的生长效果。采用多粘菌素和氨苄西林作为对照。+:生长,-:未生长。
动物效果
已在两种动物效果模型中对达罗布汀A进行了测试(图5)。在败血症模型中,向小鼠注射(ip)包含在5%粘蛋白中的106个细菌,接种物在24小时内在未治疗组中引发100%的致死率(图5A,5C)。感染后1小时,每组3只,以20mg/kg庆大霉素作为阳性对照,或以不同剂量水平达罗布汀A治疗小鼠。在五天内监测生存情况。达罗布汀A有效地治疗了感染,并在2.5mg/kg的浓度时对抗大肠杆菌(常用的ATCC 25922菌株和耐多粘菌素临床分离株AR350)实现100%的存活(图5A)。在5小时时,从剪下尾巴抽血到板中用于CFU,用达罗布汀A治疗显著降低了大肠杆菌的负载(图5B)。在1mg/kg的剂量时,达罗布汀A仍可延长生存期,但不再100%治愈(图5A)。使用耐多粘菌素的实验室菌株,以50mg/kg的剂量开展了达罗布汀A对抗铜绿假单胞菌败血症的测试,并实现100%的存活率(图5C)。然后在嗜中性白血球减少症的小鼠大腿模型中测试达罗布汀A的功效。给小鼠施用环磷酰胺(第-3天,第0天)以诱导嗜中性白血球减少症,然后在其右大腿上以106CFU大肠杆菌AR350开展感染(第1天),并在感染后2小时开始治疗。未经治疗的对照组(每组四只小鼠)在0、2和24小时被处死以监测感染的进展。将2小时时单次注射(ip)50mg/kg达罗布汀A与分别在感染后2、8、14小时三次(ip)施用25mg/kg的达罗布汀A及在2小时时单次注射(ip)20mg/kg庆大霉素进行比较,每个治疗组四只小鼠。在24小时将小鼠处死,无菌取出大腿,匀化,然后铺在琼脂平板上以计数CFU(图5D)。与未治疗的对照组相比,达罗布汀A50mg/kg使感染负载下降了1个对数级,而3次施用25mg/kg达罗布汀A使感染负载下降了2个对数级,包括其中有两只小鼠下降到低于检出限。
因此,达罗布汀A能够以2.5mg/kg(ip)的剂量治愈大肠杆菌败血症小鼠:ATCC25922和耐多粘菌素临床分离株AR350都可治愈,n=3/每个治疗组,在感染1小时后开始治疗。1mg/kg(ip)的达罗布汀A延长了生存期,并在5h时显著降低了CFU负载(A、B)。
本文使用的词语和表达作为描述性词语而非限制性词语使用,在使用所述词语和表达时,并不排除所示或所述或其部分特征的任何相当物。另外,已经描述了本发明的某些实施例,对于本领域的普通技术人员将显而易见的是,在不脱离本发明的精神和范围的情况下,可以使用结合本文公开概念的其他实施例。因此,所描述的实施例在所有方面都应被认为仅是示例性的而非限制性的。
序列表
<110> 东北大学
K•路易斯
今井优
Q•法夫雷戈达尔
飯西輝
K•梅耶尔
<120> 具有抗菌特性的化合物
<130> 121504-5003-WO
<150> 62/789,313
<151> 2019-01-07
<150> 62/700,746
<151> 2018-07-19
<160> 13
<170> SIPOSequenceListing 1.0
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<213> 发光杆菌属(Photorhabdus sp.)
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Ser Leu Ala Ala Ser Phe Lys Glu Thr Glu Leu Ser Ile Thr Asp Lys
20 25 30
Ala Leu Asn Glu Leu Ser Asn Lys Pro Lys Ile Pro Glu Ile Thr Ala
35 40 45
Trp Asn Trp Ser Lys Ser Phe Gln Glu Ile
50 55
<210> 10
<211> 58
<212> PRT
<213> Photorhabdus heterorhabditis
<400> 10
Met Gln Asn Ile Leu Val Glu Thr Cys Lys Thr Gln Glu Ala Leu Asn
1 5 10 15
Ser Leu Ala Ala Ser Phe Lys Glu Thr Glu Leu Ser Ile Thr Glu Lys
20 25 30
Ala Leu Asn Glu Leu Ser Ser Lys Pro Lys Ile Pro Glu Ile Thr Ala
35 40 45
Trp Asn Trp Ser Lys Ser Phe Gln Glu Ile
50 55
<210> 11
<211> 55
<212> PRT
<213> Photorhabdus asymbiotica
<400> 11
Met Gln Asn Ile Ser Val Asn Thr Gln Glu Ala Leu Asn Ser Leu Ala
1 5 10 15
Ala Ser Phe Lys Glu Thr Glu Leu Ser Ile Thr Glu Lys Ser Leu Asn
20 25 30
Glu Leu Ser Ser Lys Pro Lys Ile Pro Glu Ile Thr Ala Trp Asn Trp
35 40 45
Ser Lys Ser Phe Gln Glu Ile
50 55
<210> 12
<211> 55
<212> PRT
<213> Photorhabdus australis
<400> 12
Met Gln Asn Ile Ser Val Asn Thr Gln Glu Ala Leu Asn Ser Leu Ala
1 5 10 15
Ala Ser Phe Lys Glu Thr Glu Leu Ser Ile Thr Glu Lys Ser Leu Asn
20 25 30
Glu Leu Ser Ser Lys Pro Lys Ile Pro Glu Ile Thr Ala Trp Asn Trp
35 40 45
Ser Lys Ser Phe Gln Glu Ile
50 55
<210> 13
<211> 58
<212> PRT
<213> MQNILVETCK TQEALNSLAA SFKETELSIT EKALNELSSK PKIPEITAWN WSKSFQEI
<400> 13
Met Gln Asn Thr Leu Val Glu Thr Cys Lys Thr Gln Glu Ala Leu Asn
1 5 10 15
Ser Leu Ala Ala Ser Phe Lys Glu Thr Glu Leu Ser Ile Thr Glu Lys
20 25 30
Ala Leu Asn Glu Leu Ser Ser Lys Pro Lys Ile Pro Glu Ile Thr Ala
35 40 45
Trp Asn Trp Ser Lys Ser Phe Gln Glu Ile
50 55
Claims (31)
1.一种式(1)的化合物:
和/或其药学上可接受的盐、立体异构体、互变异构体或水合物,其中:
R1、R2、R3、R4、R5和R6每个独立地选自由氢、烷基、烯基、炔基、羟基、羟烷基、卤素、–CN、–O-烷基、–C(O)-烷基、–C(O)O-烷基、–C(O)OH、–C(O)NH2、–C(O)NH-烷基、–NH2、–NO2、–CF3、–NH-烷基、–N-(烷基)2、–NHC(O)-烷基和芳基组成的组,其中所述烷基、烯基、炔基和芳基每个任选被取代,
R7和R8每个独立地选自由氢、直链或支链的C1-C5烷基、直链或支链的C2-C6烯基、直链或支链的C2-C6炔基组成的组;其中所述烷基、烯基和炔基分别任选被取代;
R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19和R20每个独立地选自由氢、烷基、烯基、炔基、环烷基、环烯基、杂环烷基、杂环烯基、芳基、杂芳基、卤代烷基、羟基、羟烷基、卤素、–CN、–O-烷基、–C(O)-烷基、–C(O)O-烷基、–C(O)OH、–C(O)NH2、–C(O)NH-烷基、–NH2、–NO2、–CF3、–NH-烷基、–NHC(O)-烷基组成的组,其中所述烷基、烯基、炔基、环烷基、环烯基、杂环烷基、杂环烯基、芳基、杂芳基、卤代烷基每个任选被取代;
A是键或–(CH2)n–,其中n是0到10之间的整数;
X是–C(O)–、–CH2–、–C(OH)–、–C(O)O-烷基、–C((O)烷基)–。
3.根据权利要求1或2所述的化合物,其中R3、R4和R5每个独立地选自由羟基、羟烷基、卤素、-CN和-O-烷基组成的组。
4.根据权利要求1或2所述的化合物,其中R3是羟基。
5.根据权利要求1或2所述的化合物,其中R4是羟基。
6.根据权利要求1或2所述的化合物,其中R5是羟基。
7.根据权利要求1或2所述的化合物,其中R6是–NH2。
8.根据权利要求1或2所述的化合物,其中R7和R8每个独立地选自由氢、烷基、烯基、炔基和芳基组成的组。
9.根据权利要求1或2所述的化合物,其中R7是氢。
10.根据权利要求1或2所述的化合物,其中R8是氢。
12.一种用于治疗动物中由革兰氏阴性菌引发的感染的药物组合物,包括治疗有效量的根据权利要求1-11中任一项所述的化合物或其药学上可接受的盐。
13.根据权利要求12所述的药物组合物,进一步包括至少一种药学上可接受的载体、赋形剂或稀释剂。
14.根据权利要求12至13中任一项所述的药物组合物,其为局部施用、全身施用、肠胃外施用、皮下施用,或经皮施用、直肠施用、口服施用、阴道内施用、鼻内施用、支气管内施用、眼内施用、耳内施用、静脉内施用、肌肉内施用或腹膜内施用。
15.根据权利要求12至14中任一项所述的药物组合物,进一步包括至少一种其它治疗剂。
16.根据权利要求12至15中任一项所述的药物组合物,其通过培养能够在营养培养基中产生所述化合物的微生物而得到。
17.根据权利要求16所述的药物组合物,其中所述微生物是Photorhabdus khanii DSM3369。
18.一种治疗、改善或预防细菌感染或疾病的方法,包括向有需要的受试者施用治疗有效量的根据权利要求1-11中任一项所述的化合物或其药学上可接受的盐。
19.根据权利要求18所述的方法,其中所述细菌是革兰氏阴性菌。
20.根据权利要求19所述的方法,其中所述革兰氏阴性菌是大肠杆菌、铜绿假单胞菌、韧皮部杆菌、根癌土壤杆菌、鲍曼不动杆菌、卡他布兰汉菌、柠檬酸杆菌、产气肠杆菌、肺炎克雷伯菌、奇异变形杆菌、鼠伤寒沙门氏菌、脑膜炎奈瑟氏菌、粘质沙雷氏菌、宋内志贺氏菌、鲍氏志贺氏菌、淋病奈瑟氏菌、鲍曼不动杆菌、肠炎沙门氏菌、具核梭杆菌、极小韦永氏球菌、伴放线放线杆菌(Actinobacillus actinomycetemcomitans)、放线共生放线杆菌(Aggregatibacter actinomycetemcomitans)、牙龈卟啉单胞菌、幽门螺杆菌、土拉弗朗西斯菌、鼠疫耶尔森菌、霍乱弧菌、摩氏摩根菌(Morganella morganii)、迟缓爱德华菌、空肠弯曲杆菌或流感嗜血杆菌、阴沟肠杆菌。
21.根据权利要求18-20中任一项所述的方法,其中所述细菌是易感的或耐多药的。
22.根据权利要求18-21中任一项所述的方法,其中所述细菌是耐多药的。
23.根据权利要求18-22中任一项所述的方法,其中所述细菌是耐多粘菌素突变体。
24.根据权利要求18-23中任一项所述的方法,其中所述细菌是耐碳青霉烯菌、耐甲氧西林金黄色葡萄球菌、耐万古霉素肠球菌或耐多药性淋病奈瑟氏菌。
25.根据权利要求18-24中任一项所述的方法,其中所述细菌感染是呼吸道感染、皮肤或皮肤结构感染、尿路感染、腹腔内感染、血流感染、胃肠道感染。
26.根据权利要求18-25中任一项所述的方法,其中所述疾病选自由皮肤炎症性疾病、炎症性肠病(IBD)、溃疡性结肠炎、克罗恩氏病和乳糜泻组成的组。
27.根据权利要求18-25中任一项所述的方法,其中所述受试者是哺乳动物。
28.根据权利要求26所述的方法,其中所述受试者是人类。
29.根据权利要求26所述的方法,其中所述受试者是非人类。
30.根据权利要求18-28中任一项所述的方法,其中所述细菌感染包括易感的或耐多药的细菌。
31.根据权利要求18-29中任一项所述的方法,其中所述施用步骤包括局部施用、全身施用、肠胃外施用、皮下施用或经皮施用、直肠施用、口服施用、阴道内施用、鼻内施用、支气管内施用、眼内施用、耳内施用、静脉内施用、肌肉内施用或腹膜内施用。
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Non-Patent Citations (4)
Title |
---|
GRAHAM A HUDSON等: "RiPP antibiotics: biosynthesis and engineering potential", 《CURRENT OPINION IN MICROBIOLOGY》 * |
PATRICK TAILLIEZ 等: "Phylogeny of Photorhabdus and Xenorhabdus based on universally conserved protein-coding sequences and implications for the taxonomy of these two genera. Proposal of new taxa: X. vietnamensis sp. nov., P. luminescens subsp. caribbeanensis subsp. nov., P. lu", 《INTERNATIONAL JOURNAL OF SYSTEMATIC AND EVOLUTIONARY MICROBIOLOGY》 * |
SHELDON HURST IV 等: "Elucidation of the Photorhabdus temperata Genome and Generation of a Transposon Mutant Library To Identify Motility Mutants Altered in Pathogenesis", 《JOURNAL OF BACTERIOLOGY》 * |
YING YE等: "Unveiling the Biosynthetic Pathway of the Ribosomally Synthesized and Post-translationally Modified Peptide Ustiloxin B in Filamentous Fungi", 《ANGEW. CHEM. INT. ED.》 * |
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