CN114699402B - 黄酮类化合物用于制备β-内酰胺酶抑制剂的用途 - Google Patents
黄酮类化合物用于制备β-内酰胺酶抑制剂的用途 Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了黄酮类化合物用于制备丝氨酸β‑内酰胺酶抑制剂的用途。具体的所述黄酮类化合物为槲皮素、漆黄素、木犀草素、3',4',7‑三羟基黄酮、芹菜素、山奈酚和二氢槲皮素中的任意一种或者多种组合,尤其公开了在制备D类丝氨酸β‑内酰胺酶OXA‑48抑制剂方面的用途。本发明公开的黄酮类化合物与β‑内酰胺类药物联合对抗产生OXA‑48的耐药细菌。
Description
技术领域
本发明涉及丝氨酸β-内酰胺酶抑制剂领域,具体涉及黄酮类化合物作为丝氨酸β-内酰胺酶抑制剂的用途。
背景技术
青霉素类、头孢类和碳青霉烯类等β-内酰胺类抗生素是治疗细菌感染最有效的药物之一,也是临床上使用最为广泛的抗生素。然而,随着抗生素的过度使用,临床上发现了多种多重耐药菌,它们的主要耐药机制之一是表达β-内酰胺酶,催化水解抗生素的β-内酰胺环,从而使抗生素失效。根据β-内酰胺酶的氨基酸序列同源性和酶水解抗生素的机制,β-内酰胺酶可以分为A-D四类。A、C和D类是丝氨酸β-内酰胺酶(SβLs),通过活性位点的丝氨酸作为亲核试剂水解抗生素,而B类是金属β-内酰胺酶(MβLs),利用活性中心的锌离子进行水解。
D类β-内酰胺酶或OXA型β-内酰胺酶(OXA)是一类重要的丝氨酸β-内酰胺酶。其中,OXA-48是主要的D类β-内酰胺酶,2001年首次从土耳其分离出来,此后迅速蔓延到全世界。它通常在大肠杆菌、梭状芽孢杆菌、枸橼酸杆菌和肺炎克雷伯菌中发现。OXA-48能够水解青霉素类和碳青霉烯类抗生素,其中碳青霉烯类抗生素被称为抗生素的“最后一道防线”。
治疗产生β-内酰胺酶的耐药细菌感染的有效策略是将β-内酰胺类抗生素与β-内酰胺酶抑制剂联合使用。目前,临床上已有获准上市的SβL抑制剂,如克拉维酸、舒巴坦和他唑巴坦,它们主要对A类和C类β-内酰胺酶有活性。阿维巴坦是一种新的SβL抑制剂,它能够抑制A类、C类和一些D类SβLs,包括OXA-48,但是其替代方案少,而且价格非常昂贵。因此,迫切需要开发OXA-48等D类丝氨酸β-内酰胺酶的抑制剂。
天然产物在药物发现史中发挥了重要作用,其中,黄酮类化合物是从自然界中获得的一大类结构多样的天然产物,这类化合物骨架结构是2-苯基色原酮(C6-C3-C6)。然而,天然产物作为β-内酰胺酶抑制剂的报道相对较少,黄酮类化合物作为D类SβL的抑制剂还未见报道。槲皮素是一种典型的黄酮类化合物,广泛存在于水果、蔬菜和茶叶中,尤其是洋葱、红茶和苹果中。它具有许多生物学和药理作用,包括抗氧化、抗癌、抗炎、抗病毒和抗动脉粥样硬化。但是,目前还未见槲皮素及其结构类似物作为D类SβL抑制剂方面的报道。
虽然槲皮素等天然产物中已经有部分能够和抗生素联合使用增强抗生素的杀菌性能,但是其大多利用了黄酮类化合物本身就具有抗菌活性,比如依靠改变细菌的细胞形态来实现,不利于临床上针对分离到的耐药细菌选择有效的抗生素。
发明内容
针对现有技术中存在的OXA-48具有水解碳青霉烯类抗生素,使抗生素失效,从而严重威胁到β-内酰胺类抗生素治疗细菌感染的疗效。克拉维酸、舒巴坦和他唑巴坦等商业抑制剂主要对A类和C类β-内酰胺酶具有抑制活性,针对D类丝氨酸β-内酰胺酶的抑制剂种类较少,而且价格非常昂贵的技术问题。本发明公开了黄酮类化合物用于制备丝氨酸β-内酰胺酶抑制剂的用途,本发明发现黄酮类化合物与青霉素类或碳青霉烯类抗生素联用,能够使青霉素类或碳青霉烯类抗生素免于被丝氨酸β-内酰胺酶水解,从而维持抗生素的疗效。本发明通过表达OXA-48的高敏菌株大肠杆菌BW25113ΔacrAΔbamB,筛选了一个由约150个候选化合物组成的天然产物平台,发现黄酮类化合物在产生OXA-48的敏感大肠杆菌菌株中恢复了β-内酰胺类抗生素的活性,使MIC降低了2-8倍而不影响细菌的生长,进一步在体内验证了哌拉西林和槲皮素联合使用对治疗产OXA-48的大肠杆菌具有较好的疗效,明显降低了小鼠肝脏和脾脏中的细菌数量。另外,利用天然产物的黄酮类化合物作为制备丝氨酸β-内酰胺酶抑制剂,其副作用小,来源广泛。
具体的,第一方面,本发明提供了黄酮类化合物用于制备丝氨酸β-内酰胺酶抑制剂的用途。
优选的,本发明所述黄酮类化合物的2,3位为不饱和双键。
优选的,本发明所述黄酮类化合物的R1,R2,R3,R4和R5位点同时或部分含有取代基。
优选的,本发明所述黄酮类化合物的R1,R2,R3,R4和R5位点的取代基为羟基。
具体的,本发明所述黄酮类化合物为槲皮素、漆黄素、木犀草素、3',4',7-三羟基黄酮、芹菜素、山奈酚和二氢槲皮素中的任意一种或者多种组合。
更进一步的,本发明所述黄酮类化合物为槲皮素及其结构类似物。
第二方面,本发明提供了黄酮类化合物用于制备D类丝氨酸β-内酰胺酶抑制剂的用途。
第三方面,本发明提供了黄酮类化合物用于制备D类丝氨酸β-内酰胺酶OXA-48抑制剂的用途。
更加具体的,本发明提供了黄酮类化合物在恢复哌拉西林和亚胺培南对携带OXA-48的大肠杆菌抗菌性的应用。
第四方面,本发明提供了一种抗菌药物组合物,所述组合物中含有丝氨酸β-内酰胺酶抑制剂,所述丝氨酸β-内酰胺酶抑制剂为一种或者一种以上的黄酮类化合物,同时该抗菌药物组合物还含有β-内酰胺类抗生素。
优选的,本发明抗菌药物组合物中所述黄酮类化合物为槲皮素及其结构类似物。
第六个方面,本发明提供了一种OXA-48抑制剂结构的设计方法,所述设计方法是选择符合如下结构通式的物质:
上式中:2,3位含有双键;所述R1,R2,R3,R4和R5分别为-H或者-OH。
本发明的有益效果:
本发明提供的黄酮类化合物作为SβL抑制剂的用途,通过抑制试验显示,包括槲皮素、漆黄素、木犀草素、3',4',7-三羟基黄酮、芹菜素、山奈酚和二氢槲皮素在内的多个黄酮类化合物对SβL具有抑制活性,尤其对OXA-48具有较好的抑制作用,IC50值<5μM。
本发明提供的槲皮素、漆黄素、木犀草素和3',4',7-三羟基黄酮等黄酮类物质对D类SβL具有抑制活性,尤其对OXA-48表现出很好的抑制活性,IC50值从0.47到1.89μM不等。
本发明提供的SβL抑制剂槲皮素、漆黄素、木犀草素和3',4',7-三羟基黄酮有效地恢复了哌拉西林和亚胺培南对携带OXA-48的大肠杆菌的抗菌功效,使其MIC降低2-8倍,槲皮素以非竞争性抑制模式抑制OXA-48。
本发明提供的抗菌药物组合物作为含有OXA-48抑制剂的药物,与β-内酰胺类药物一起对抗产生OXA-48的耐药细菌。
本发明还提供了一种OXA-48抑制剂结构的设计方法,不但能够针对性选择天然物质进行相应筛选实验,还能够针对性的设计合成相应的化合物进行OXA-48抑制活性的测定,从而减少了SβL抑制剂筛选获取难度,加快了丝氨酸β-内酰胺酶抑制剂筛选速度,为OXA-48抑制剂提供了更为广阔的来源。
附图说明
图1为黄酮类化合物的基本结构。
图2为本发明槲皮素对OXA-48的抑制活性。
图3为本发明对槲皮素-哌拉西林组合的协同抑菌作用。
图4为本发明槲皮素对测试菌生长曲线的影响。
图5为本发明槲皮素与哌拉西林联合使用的体内抗菌效果。
具体实施方式
下面结合附图1-3和实施例对本发明的具体实施方式作进一步详细描述,但本发明的方法不限于下述实施例。
在本发明中,所用到试剂都是通过普通市场途径采购获得。本发明详述分成各个实施例部分仅仅为了读者方便,并且在任何部分存在的内容可以与另一部分存在的内容组合。除非另外指出,本发明所用的所有技术和科学术语具有的含义与本发明所属领域的普通技术人员通常理解的含义相同。
必须注意的是,除非上下文另有明确说明,如本发明实施例和所附权利要求中所使用的,单数形式“一个”、“一种”和“这种”包括复数指代。因此,例如,提及“一种抗菌药物组合物”包括多种这样的候选试剂,并且提及“这种槲皮素及其结构类似物”包括提及一种或更多种槲皮素、山奈酚、白杨素、高良姜素、芹菜素、木犀草素、二氢槲皮素、柚皮素、漆黄素、3’,4’,7--三羟基黄酮、异槲皮素等其他本领域技术人员已知的结构类似物,等等。
如本发明实施例所用,当在数字名称例如温度、时间、量、浓度等等之前使用的术语为“大约”时表示可以以(+)或(-)10%、5%或1%变化的近似值。
当在本发明实施中列出一个范围(例如,剂量范围)时,应当理解,该值可以包括在所述范围内的任何单个值或范围,包括端点。
本发明提供了黄酮类化合物用于制备丝氨酸β-内酰胺酶抑制剂的用途。本发明所述黄酮类化合物的2,3位为不饱和双键。所述黄酮类化合物的R1,R2,R3,R4和R5位点同时或部分含有取代基。本发明所述黄酮类化合物的R1,R2,R3,R4和R5位点的取代基为羟基。
具体的,本发明下列实施例中筛选出的黄酮类化合物为槲皮素、漆黄素、木犀草素、3',4',7-三羟基黄酮、芹菜素、山奈酚和二氢槲皮素。
通过筛选试验发现,本发明槲皮素及其结构类似物对于D类丝氨酸β-内酰胺酶OXA-48有更加明显的抑制效果。
更加具体的,本发明实施例获得了黄酮类化合物在恢复哌拉西林和亚胺培南对携带OXA-48的大肠杆菌抗菌性的应用。
实施例1:一种抗菌药物组合物
本实施例公开了一种抗菌药物组合物,所述组合物中含有丝氨酸β-内酰胺酶抑制剂和β-内酰胺类抗生素,所述丝氨酸β-内酰胺酶抑制剂为黄酮类化合物。
本实施例所述黄酮类化合物为槲皮素、3',4',7-三羟基黄酮、漆黄素和芹木犀草素组合物。
实施例2:一种OXA-48抑制剂结构的设计方法
本实施例提供了一种OXA-48抑制剂结构的设计方法,所述设计了符合如下结构通式的物质:
上式中:2,3位含有双键;所述R1,R2,R3,R4和R5为羟基的物质,并对合成的化合物进行OXA-48抑制活性的测定。
实施例3:槲皮素及其结构类似物对OXA-48抑制活性的测定(IC50)
以头孢硝噻吩作为水解底物,在495nm波长处监测OXA-48型丝氨酸β-内酰胺酶水解底物后吸光度的变化。测定缓冲液为0.1MPBS(pH7.0),30mM NaHCO3,温度为25℃。具体方法如下:酶和抑制剂在缓冲液中孵育30min,使抑制剂与酶充分作用,将混合液加入96孔板中,添加底物后,立即用酶标仪记录反应前30s的吸光度变化,计算初始反应速率。整个实验保持底物和酶浓度不变,改变抑制剂的浓度,计算不同抑制剂浓度下的百分抑制率,通过GraphPad Prism 7.0进行非线性拟合,计算IC50值(半效抑制浓度)。检测的槲皮素结构类似物包括芹菜素,木犀草素,山奈酚,二氢槲皮素,漆黄素以及3’,4’,7-三羟基黄酮,IC50值见表1,其中,槲皮素的IC50抑制曲线见图2,结果显示槲皮素及其结构类似物对OXA-48具有显著的抑制活性,IC50为0.47–4.54μM。
表1.抑制活性测定
实施例4:最小抑菌浓度(MIC)测定
本实施例CLSI(美国临床实验室标准化协会)标准描述的方法,添加16和64μg/mL的化合物(漆黄素、3',4',7-三羟基黄酮、木犀草素或槲皮素),测定β-内酰胺抗生素对耐药革兰氏阴性菌的最小抑制浓度(MIC)。本实施例将表达OXA-48的BW25113ΔacrAΔbamB大肠杆菌作为检测菌株,哌拉西林或亚胺培南作为β-内酰胺抗生素的代表。
具体方法如下:
(1)菌液制备:挑取表达OXA-48的E.coli BW25113ΔacrAΔbamB至LB液体培养基中,150rpm过夜摇培,次日将培养液以1%比例转接至新鲜的LB液体培养基中,待OD600达到0.5时终止培养。
(2)抗生素的制备:灭菌的MH液体培养基配制浓度为2048μg/mL的哌拉西林或16μg/mL亚胺培南,2倍梯度稀释,现用现配。
(3)抑制剂的制备:灭菌的MH液体培养基配制母液浓度为64μg/mL和256μg/mL的槲皮素,漆黄素,木犀草素和3’,4’,7-三羟基黄酮。
(4)无菌的96孔培养板中加入梯度稀释的化合物50μL,梯度稀释的抗生素50μL,再加入100μL菌液,使每孔菌液终浓度为5×105cfu/mL,第1至第6孔的哌拉西林浓度分别为512,256,128,64,32,16μg/mL,亚胺培南浓度分别为4,2,1,0.5,0.25,0.125μg/mL,将加好样品的96孔板置于37℃培养箱培养16-18h,酶标仪上测定600nm波长下的吸光值。
表2.MIC检测
MIC结果见表2,从结果可以看出,添加64μg/mL的化合物,β-内酰胺类抗生素对E.coliBW25113ΔacrAΔbamB(OXA-48)的MIC值均得到降低。槲皮素和3',4',7-三羟基黄酮能够使哌拉西林的MIC值降低8倍,漆黄素或木犀草素与哌拉西林联合使用,哌拉西林的MIC值降低了2倍和4倍。槲皮素、漆黄素或木犀草素在64μg/mL的剂量下,导致亚胺培南的MIC值下降2倍。
为了评估所观察到的协同作用,槲皮素与哌拉西林联合测试了对产OXA-48的E.coli的抑菌作用。如说明书附图3所示,槲皮素-哌拉西林的协同指数(FICI)为0.375(FICI<0.5),说明这两种化合物之间具有协同抑菌作用。另外,如附图4所示,本实施例也验证了在64μg/mL的浓度下,黄酮类化合物不会影响受试细菌的生长,将槲皮素单独加入本实施例采用的细菌中,监测其生长曲线。结果显示,槲皮素本身没有抑菌作用。
实施例5:槲皮素与哌拉西林联合使用的体内抗菌效果
本实施例采用小鼠腹腔急性感染模型,在体内验证了槲皮素与哌拉西林的抑菌疗效。选用8周龄昆明小鼠,适应性喂养3天后,小鼠按体重随机分为4组,每组6只,将细菌培养至OD600为1,用PBS洗涤3次后,等体积PBS重悬,然后取150μL菌液注入小鼠腹腔内。感染1h后,分别腹腔注射100μL(1)PBS+5%DMSO(模型组),(2)槲皮素(10mg/kg),(3)哌拉西林(10mg/kg),(4)槲皮素+哌拉西林组合物(10mg/kg+10mg/kg,)对小鼠的感染组进行治疗。干预24h后,取小鼠的肝和脾,分别称重。将组织置于1mL冰预冷的无菌PBS,匀浆,梯度稀释后涂布,计算菌落数。
如图5所示,与未治疗组相比,哌拉西林或槲皮素单独治疗的感染小鼠的细菌量没有明显减少。然而,哌拉西林和槲皮素联合治疗时,肝脏和脾脏中的细菌克隆数显著减少(P<0.05),进一步在体内验证了哌拉西林和槲皮素联合使用对治疗产生OXA-48的大肠杆菌具有较好的疗效。
如上所述,即可较好地实现本发明,上述的实施例仅仅是对本发明的优选实施方式进行描述,并非对本发明的范围进行限定,在不脱离本发明设计精神的前提下,本领域普通技术人员对本发明的技术方案作出的各种变形和改进,均应落入本发明确定的保护范围内。
Claims (1)
1.一种黄酮类化合物用于制备抑制含有D类丝氨酸β-内酰胺酶OXA-48耐药细菌的药物的用途,所述药物包括所述黄酮类化合物和抗生素,所述黄酮类化合物为3',4',7-三羟基黄酮;所述抗生素为哌拉西林或者亚胺培南;所述哌拉西林浓度为64μg/mL,所述亚胺培南浓度1μg/mL,所述黄酮类化合物的浓度为64μg/mL。
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Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2428564A1 (en) * | 2003-05-14 | 2004-11-14 | Tomihiko Higuchi | Pharmaceutical composition for treatment of infection with drug resistant bacterium and disinfectant |
CN105669622A (zh) * | 2014-11-21 | 2016-06-15 | 中国人民解放军第二军医大学 | 奇蒿提取物4′,5,7-三羟基黄酮的制备与应用 |
CN109939098A (zh) * | 2019-03-08 | 2019-06-28 | 广东工业大学 | 黄酮碳苷类化合物在制备抑制细菌群体感应的产品中的应用 |
CN111096964A (zh) * | 2019-12-06 | 2020-05-05 | 中国农业大学 | 一种槲皮素与抗菌药物的联合应用 |
KR20200046287A (ko) * | 2018-10-24 | 2020-05-07 | 건국대학교 산학협력단 | 3',4'-디플루오로케르세틴 및 그 유도체에 의한 항생제 내성 억제 효능 |
CN112843047A (zh) * | 2021-03-31 | 2021-05-28 | 重庆市公共卫生医疗救治中心 | 槲皮素在增强抗菌药物的杀菌能力中的应用 |
CN113855669A (zh) * | 2021-09-30 | 2021-12-31 | 成都医学院 | 一种抗菌的联合用药物 |
-
2022
- 2022-04-06 CN CN202210357733.5A patent/CN114699402B/zh active Active
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2428564A1 (en) * | 2003-05-14 | 2004-11-14 | Tomihiko Higuchi | Pharmaceutical composition for treatment of infection with drug resistant bacterium and disinfectant |
CN105669622A (zh) * | 2014-11-21 | 2016-06-15 | 中国人民解放军第二军医大学 | 奇蒿提取物4′,5,7-三羟基黄酮的制备与应用 |
KR20200046287A (ko) * | 2018-10-24 | 2020-05-07 | 건국대학교 산학협력단 | 3',4'-디플루오로케르세틴 및 그 유도체에 의한 항생제 내성 억제 효능 |
CN109939098A (zh) * | 2019-03-08 | 2019-06-28 | 广东工业大学 | 黄酮碳苷类化合物在制备抑制细菌群体感应的产品中的应用 |
CN111096964A (zh) * | 2019-12-06 | 2020-05-05 | 中国农业大学 | 一种槲皮素与抗菌药物的联合应用 |
CN112843047A (zh) * | 2021-03-31 | 2021-05-28 | 重庆市公共卫生医疗救治中心 | 槲皮素在增强抗菌药物的杀菌能力中的应用 |
CN113855669A (zh) * | 2021-09-30 | 2021-12-31 | 成都医学院 | 一种抗菌的联合用药物 |
Non-Patent Citations (6)
Title |
---|
Arijit Pal等.Quercetin inhibits carbapenemase and efflux pump activity among carbapenem-resistant Gram-negative bacteria.APMIS..2020,第128卷(第3期),第6页第4段,第7页第2段,第8页第2、4段,第9页第3段,第14页图1a. * |
Dzotam等.In vitro antibacterial and antibiotic modifying activity of crude extract, fractions and 3′,4′,7-trihydroxyflavone from Myristica fragrans Houtt against MDR Gram-negative enteric bacteria.BMC Complementary and Alternative Medicine.2018,第18卷(第1期),摘要. * |
Evaluation of quercetin as a potential β-lactamase CTX-M-15 inhibitor via the molecular docking, dynamics simulations, and MMGBSA;SARIYER, E.等;Turk J Chem.;第45卷(第4期);摘要 * |
In vitro antibacterial and antibiotic modifying activity of crude extract, fractions and 3′,4′,7-trihydroxyflavone from Myristica fragrans Houtt against MDR Gram-negative enteric bacteria;Dzotam等;BMC Complementary and Alternative Medicine;第18卷(第1期);摘要 * |
Metallo-β-lactamases inhibitor fisetin attenuates meropenem resistance in NDM-1-producing Escherichia coli;Yan Guo等;European Journal of Medicinal Chemistry;第231卷;摘要 * |
Quercetin inhibits carbapenemase and efflux pump activity among carbapenem-resistant Gram-negative bacteria;Arijit Pal等;APMIS.;第128卷(第3期);第6页第4段,第7页第2段,第8页第2、4段,第9页第3段,第14页图1a * |
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