CN111000841A - 木犀草素在抑制多重耐药阴沟肠杆菌生长中的应用 - Google Patents
木犀草素在抑制多重耐药阴沟肠杆菌生长中的应用 Download PDFInfo
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- enterobacter cloacae
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- luteolin
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- IQPNAANSBPBGFQ-UHFFFAOYSA-N luteolin Chemical compound C=1C(O)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(O)C(O)=C1 IQPNAANSBPBGFQ-UHFFFAOYSA-N 0.000 title claims abstract description 37
- LRDGATPGVJTWLJ-UHFFFAOYSA-N luteolin Natural products OC1=CC(O)=CC(C=2OC3=CC(O)=CC(O)=C3C(=O)C=2)=C1 LRDGATPGVJTWLJ-UHFFFAOYSA-N 0.000 title claims abstract description 37
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Abstract
本发明公开了木犀草素在抑制多重耐药阴沟肠杆菌生长中的应用，根据木犀草素对耐头孢唑啉、头孢噻肟、溴格门汀、美罗培能、氧氟沙星、左氧氟沙星、环丙沙星、头孢西汀、米诺环素、亚胺培南、哌拉西林、阿奇霉素、呋喃妥因、磺胺甲基异恶唑、萘啶酸的多重耐药阴沟肠杆菌具有较好的体外杀灭作用，能够抑制多重耐药阴沟肠杆菌的生长，且最低杀菌浓度为0.5mg/mL，最小抑菌浓度为0.3mg/mL，本发明提出了木犀草素对多重耐药阴沟肠杆菌的抑制作用，在医药等领域具有广泛的应用价值。
Description
技术领域
本发明涉及医药和食品安全领域，具体涉及木犀草素在抑制多重耐药阴沟肠杆菌生长中的应用。
背景技术
阴沟肠杆菌(Enterobacter cloacae)是一种常见的革兰氏阴性杆状细菌(肠杆菌科肠杆菌属)，常从人和动物粪便中检出，能够引起机会性感染，包括下呼吸道感染、尿路感染和脑膜炎。阴沟肠杆菌还可以从食品加工厂、大米、海产品和肉制品中分离出来，它们会导致食品腐败。因此，阴沟肠杆菌最近被用作食品加工中的卫生指标，也是生肉制品和加工蔬菜中最具挑战性的细菌污染物之一。
近年来，越来越多的研究发现阴沟肠杆菌的多重耐药率不断上升。尤其重要的是碳青霉烯类抗生素的耐药性，这主要是由碳青霉烯酶的产生引起的。阴沟肠杆菌中最常见的碳青霉烯酶是ndm-1、imp和kpc(Jia X,Dai W et al.Carbapenem-resistant E.cloacaein southwest China:molecular analysis of resistance and risk factors forinfections caused by NDM-1-producers.2018:9,658.)，可导致出现耐碳青霉烯酶的阴沟肠杆菌(cr ec；Jiang Y,Jia X et al.Risk factors with the development ofinfection with tigecycline-and carbapenem-resistant Enterobactercloacae.2019,12:667-674.)。
抗生素的广泛使用、过度使用使得细菌对抗生素耐药性不断增加，抗生素耐药问题成为医疗卫生领域的一个重大挑战。天然药物资源丰富，活性物质结构新颖、疗效高，不良反应少，所以已成为制药工业中新药研究的主要来源之一。天然活性化合物作为先导物通过适当结构可成为新药开发新的来源。
木犀草素是腰果壳、椰子壳、花生壳等的提取物的主要成分。木犀草素属于柑橘类生物类黄酮，呈黄色结晶。木犀草素的中文名称为3',4',5,7-四羟黄酮，别名有黄色黄素和黄示灵，英文名称为Luteolin，分子式是C15H10O6，分子量是286.23，熔点为330℃。
据报道木犀草素可用作抗氧化剂、自由基清除剂，炎症和免疫系统调节剂，并对多种癌症具有活性。此外，木犀草素对多种微生物有抗菌特性，比如大肠杆菌、单增李斯特菌、金黄色葡萄球菌，其中，大肠杆菌是肠杆菌科埃希氏菌属，单增李斯特是肠杆菌科李斯特氏菌属，金黄色葡萄球菌是葡萄球菌属。但是，未有文献报道木犀草素对多重耐药阴沟肠杆菌具有抑菌作用。
发明内容
本发明针对目前临床医学及食品安全领域面临的耐药难题，目的在于提供木犀草素在抑制多重耐药阴沟肠杆菌生长中的应用。
为了实现上述目的，本发明采用的技术方案为：
利用纸片扩散法确定阴沟肠杆菌对抗生素的耐药性，通过微量二倍稀释法确定木犀草素对阴沟肠杆菌的最小抑菌浓度(MIC)和最低杀菌浓度(MBC)。结果表明：木犀草素对多重耐药阴沟肠杆菌具有较好的抑菌作用，可以用于抑制多重耐药阴沟肠杆菌的生长。
优选的，所述多重耐药阴沟肠杆菌为耐头孢唑啉、头孢噻肟、溴格门汀、美罗培能、氧氟沙星、左氧氟沙星、环丙沙星、头孢西汀、米诺环素、亚胺培南、哌拉西林、阿奇霉素、呋喃妥因、磺胺甲基异恶唑、萘啶酸中多种抗生素的人源阴沟肠杆菌。
优选的，所述多重耐药阴沟肠杆菌选自耐头孢唑啉、头孢噻肟、溴格门汀、美罗培能、氧氟沙星、左氧氟沙星、环丙沙星、头孢西汀、米诺环素、亚胺培南、哌拉西林、阿奇霉素、呋喃妥因、磺胺甲基异恶唑及萘啶酸的人源阴沟肠杆菌。
优选的，所述木犀草素的最小抑菌浓度为0.3mg/mL，最低杀菌浓度为0.5mg/mL。
本发明的有益效果体现在：
本发明从现存的药用植物资源库入手，挖掘潜在的耐药菌抑制剂，基于木犀草素对多重耐药阴沟肠杆菌的作用的研究，发现利用非抗生素类化合物木犀草素可以有效抑制多重耐药阴沟肠杆菌的生长，为多重耐药阴沟肠杆菌抑制剂的研究开发和应用提供新的思路和来源，在食品、医药等领域具有广泛的应用价值。
进一步的，本发明明确了木犀草素对多重耐药阴沟肠杆菌的抑制作用，将其作为抗生素替代品，可有效缓解或解决多重耐药阴沟肠杆菌的耐药及感染问题，降低病死率。
具体实施方式
下面结合实施例对本发明做进一步详细说明。所述实施例仅用于解释本发明，并非对本发明保护范围的限制。
1、阴沟肠杆菌的药敏实验
本发明以多株人源阴沟肠杆菌(菌株样本取自宁波妇儿医院)为出发菌株，选用头孢唑啉、头孢噻肟、溴格门汀、美罗培能、氧氟沙星、左氧氟沙星、环丙沙星、头孢西汀、米诺环素、亚胺培南、哌拉西林、阿奇霉素、呋喃妥因、庆大霉素等16种常用抗生素的药敏试纸片进行药敏试验。
挑取培养18～24h的纯菌落均匀溶解于2～5mL无菌生理盐水中，调节其浊度与0.5麦氏比浊管等浊。无菌吸取50～200μL菌液，均匀涂布平板，室温下放置3～5min。用无菌镊子按要求将药敏试纸片(直径为6mm)紧贴于平板表面，每种药敏试纸片三个平行。将接种好的平板放置于36～37℃孵育16～24h。用0.02mm精度的游标卡尺测定抑菌圈直径，以抑菌圈的直径来判断药物的敏感性，抑菌结果根据美国临床试验室国家标准化管理委员会(CLSl2017)标准判定，判定标准见表1。实验结果见表2，结果显示，1#人源阴沟肠杆菌可以耐受10种以上临床上常见的抗生素，因此将其作为下一步实验的研究对象。
表1.美国临床试验室国家标准化管理委员会(CLSl2017)标准判定结果
表2.人源阴沟肠杆菌的药敏实验中抑菌圈直径结果
注：抑菌圈直径的单位为mm，数值均为三个平行的平均值
2、木犀草素对多重耐药菌株的抑制作用
为了充分考虑用药安全，本发明以木犀草素这一单一活性成分为研究对象，以庆大霉素作为阳性对照，以1#菌株为实验菌株，进行耐药性抑制作用的研究。挑取培养18～24h的纯菌落均匀溶解于2～5mL TSB液体培养基中，调节其浊度与0.5麦氏比浊管等浊，并用酶标仪测定其OD600值。用二甲基亚砜配制浓度为50mg/mL的木犀草素作为药液，利用试管二倍稀释法将药液、菌液及TSB液体培养基加入96孔培养板中过夜培养，不同浓度的药液组别均为三个平行，确保实验数据的可信度。
利用酶标仪测定木犀草素对多重耐药阴沟肠杆菌的最小抑菌浓度(MIC)。并以MIC浓度为参照，对进行培养的菌液增加药物稀释梯度，将相应培养液转接于无菌的TSA固体培养基中培养24h，若无单菌落生成，此浓度为木犀草素对多重耐药阴沟肠杆菌的最低杀菌浓度(MBC)，实验结果见表3。
表3.木犀草素和庆大霉素对多重耐药阴沟肠杆菌的抑制结果
由表3可知，木犀草素对耐头孢唑啉、头孢噻肟、溴格门汀、美罗培能、氧氟沙星、左氧氟沙星、环丙沙星、头孢西汀、米诺环素、亚胺培南、哌拉西林、阿奇霉素、呋喃妥因、磺胺甲基异恶唑及萘啶酸的多重耐药阴沟肠杆菌的抑制作用较好，其MIC为0.3mg/mL，MBC为0.5mg/mL，即对多重耐药的阴沟肠杆菌(例如，1#菌株)有一定的抑菌作用。
根据以上实验结果，结合中草药来源广泛、不良反应少及不易产生耐药性等特点，可通过获得活性单品成分木犀草素，直接针对临床主要的多重耐药阴沟肠杆菌发挥抑制作用，能够有效缓解或解决多重耐药阴沟肠杆菌的感染问题，降低病死率，为研究临床分离的阴沟肠杆菌的抑菌剂提供科学依据，为开发抑制多重耐药阴沟肠杆菌的药物和抗生素替代品提供新思路和来源。
Claims (10)
1.木犀草素在抑制多重耐药阴沟肠杆菌生长中的应用。
2.根据权利要求1所述的应用，其特征在于：所述多重耐药阴沟肠杆菌为人源阴沟肠杆菌。
3.根据权利要求1所述的应用，其特征在于：所述阴沟肠杆菌的耐药性是通过纸片扩散法确定的。
4.根据权利要求1所述的应用，其特征在于：所述多重耐药阴沟肠杆菌耐受的抗生素选自头孢唑啉、头孢噻肟、溴格门汀、美罗培能、氧氟沙星、左氧氟沙星、环丙沙星、头孢西汀、米诺环素、亚胺培南、哌拉西林、阿奇霉素、呋喃妥因、磺胺甲基异恶唑、萘啶酸中的多种。
5.根据权利要求1所述的应用，其特征在于：所述多重耐药阴沟肠杆菌选自耐头孢唑啉、头孢噻肟、溴格门汀、美罗培能、氧氟沙星、左氧氟沙星、环丙沙星、头孢西汀、米诺环素、亚胺培南、哌拉西林、阿奇霉素、呋喃妥因、磺胺甲基异恶唑及萘啶酸的阴沟肠杆菌。
6.根据权利要求5所述的应用，其特征在于：所述木犀草素对多重耐药阴沟肠杆菌的最小抑菌浓度为0.3mg/mL，最低杀菌浓度为0.5mg/mL。
7.根据权利要求1所述的应用，其特征在于：所述木犀草素对多重耐药阴沟肠杆菌具有体外杀灭作用，以及抑制多重耐药阴沟肠杆菌的体外生长。
8.木犀草素在制备抗多重耐药阴沟肠杆菌的药物中的应用。
9.根据权利要求8所述的应用，其特征在于：所述多重耐药阴沟肠杆菌为人源阴沟肠杆菌。
10.根据权利要求8所述的应用，其特征在于：所述多重耐药阴沟肠杆菌选自对头孢唑啉、头孢噻肟、溴格门汀、美罗培能、氧氟沙星、左氧氟沙星、环丙沙星、头孢西汀、米诺环素、亚胺培南、哌拉西林、阿奇霉素、呋喃妥因、磺胺甲基异恶唑、萘啶酸中多种抗生素耐药的阴沟肠杆菌。
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