CN110934859A - 木犀草素在抑制多重耐药雷氏普罗威登斯菌生长中的应用 - Google Patents
木犀草素在抑制多重耐药雷氏普罗威登斯菌生长中的应用 Download PDFInfo
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- CN110934859A CN110934859A CN201911329161.4A CN201911329161A CN110934859A CN 110934859 A CN110934859 A CN 110934859A CN 201911329161 A CN201911329161 A CN 201911329161A CN 110934859 A CN110934859 A CN 110934859A
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- providencia rettgeri
- luteolin
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- ampicillin
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- 241000588777 Providencia rettgeri Species 0.000 title claims abstract description 53
- MWDZOUNAPSSOEL-UHFFFAOYSA-N kaempferol Natural products OC1=C(C(=O)c2cc(O)cc(O)c2O1)c3ccc(O)cc3 MWDZOUNAPSSOEL-UHFFFAOYSA-N 0.000 title claims abstract description 34
- 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 34
- 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 34
- 235000009498 luteolin Nutrition 0.000 title claims abstract description 34
- 230000017066 negative regulation of growth Effects 0.000 title abstract description 4
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- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 claims description 14
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 claims description 8
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- 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
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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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Abstract
本发明公开木犀草素在抑制多重耐药雷氏普罗威登斯菌生长中的应用，根据木犀草素对多重耐药雷氏普罗威登斯菌具有较好的体外杀灭作用，能够抑制多重耐药雷氏普罗威登斯菌的生长，且最低杀菌浓度为30～250μg/mL，最小抑菌浓度为15～125μg/mL，本发明提出了木犀草素对多重耐药雷氏普罗威登斯菌的抑制作用，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、食品安全领域，具体涉及木犀草素在抑制多重耐药雷氏普罗威登斯菌生长中的应用。
背景技术
雷氏普罗威登斯菌(Providencia rettgeri)属于肠杆菌科，与多重疾病有关，可致泌尿道感染和其他的肠道外感染，并引起许多医院感染的爆发流行(Tshisevhe V S,Lekalakala M R,Tshuma N,et al.Outbreak of carbapenem-resistant Providenciarettgeri in a tertiary hospital[J].S Afr Med J,2017,107(1):31-33；O"Hara C M,Brenner F W,Miller J M.Classification,Identification,and ClinicalSignificance of Proteus,Providencia,and Morganella[J].Clinical MicrobiologyReviews,2000,13(4):534-546.)。雷氏普罗威登斯菌对许多抗菌药物，包括氨苄西林、第一代头孢菌素、多粘菌素和土霉素(Magiorakos A P,Srinivasan A,Carey R B,etal.Multidrug-resistant,extensively drug-resistant and pandrug-resistantbacteria:an international expert proposal for interim standard definitionsfor acquired resistance[J].Clinical Microbiology and Infection,2012,18(3):268-281.)均耐受。近年来雷氏普罗威登斯菌由于耐碳青霉烯类菌株的出现，变得越来越受关注。
近年来，因新的化学药物开发难度越来越大以及化学药物的毒副作用日益显现，人们开始把更多的眼光投向传统医药领域。木犀草素的中文名称为3',4',5,7-四羟黄酮，英文名称为Luteolin，分子式是C15H10O6，分子量是286.23，熔点为330℃。木犀草素是一种生物类黄酮类物质，它具有多种药理活性，包括抗肿瘤、抗氧化、抗炎、保护神经系统等(王继双,何焱,张文静,张鹏,黄启来,华子春.木犀草素的药理作用研究进展[J].生命科学,2013,25(06):560-565.)。据报道木犀草素对多种微生物，如枯草芽胞杆菌、大肠杆菌、金黄色葡萄球菌和铜绿假单胞菌等细菌有抗菌活性，其中，枯草芽胞杆菌属于肠杆菌科芽胞杆菌属，大肠杆菌属于肠杆菌科埃希氏菌属，金黄色葡萄球菌属于革兰氏阳性葡萄球菌属，铜绿假单胞菌属于假单胞菌属。但是，未有文献报道木犀草素对多重耐药雷氏普罗威登斯菌具有抑菌作用。
发明内容
本发明针对目前临床医学和食品安全中面临的耐药难题，目的在于提供木犀草素在抑制多重耐药雷氏普罗威登斯菌生长中的应用。
为了实现上述目的，本发明采用的技术方案为：
利用微量二倍稀释法确定雷氏普罗威登斯菌对抗生素的耐药性，然后确定了木犀草素对雷氏普罗威登斯菌的最小抑菌浓度(MIC)和最低杀菌浓度(MBC)。结果表明：木犀草素对多重耐药雷氏普罗威登斯菌具有较好的抑菌作用，可以用于抑制多重耐药雷氏普罗威登斯菌的生长。
优选的，所述多重耐药雷氏普罗威登斯菌为耐氨苄西林、氨苄西林/舒巴坦、头孢唑林、头孢替坦、头孢曲松、头孢他啶、哌拉西林/他唑巴坦、复方新诺明、头孢吡肟、氨曲南、庆大霉素、厄他培南、亚胺培南、妥布霉素、阿米卡星、环丙沙星、呋喃妥因、左氧氟沙星中多种抗生素的人源雷氏普罗威登斯菌。
优选的，所述多重耐药雷氏普罗威登斯菌选自耐氨苄西林、氨苄西林/舒巴坦、头孢唑林、头孢替坦、头孢曲松、头孢他啶、妥布霉素、哌拉西林/他唑巴坦、环丙沙星、左氧氟沙星、阿米卡星、复方新诺明、头孢吡肟、厄他培南、亚胺培南、氨曲南及庆大霉素的人源雷氏普罗威登斯菌。
优选的，所述木犀草素的最低杀菌浓度为30～250μg/mL，最小抑菌浓度为15～125μg/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雷氏普罗威登斯菌的作用的研究，发现非抗生素类化合物木犀草素可以有效抑制多重耐药雷氏普罗威登斯菌的生长，为多重耐药雷氏普罗威登斯菌抑制剂的研究开发和应用提供新的思路和来源，在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雷氏普罗威登斯菌的抑制作用，可有效缓解或解决多重耐药雷氏普罗威登斯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、雷氏普罗威登斯菌的药敏实验
本发明以多株人源雷氏普罗威登斯菌(菌株样本取自宁波妇儿医院)为出发菌株，选用氨苄西林、氨苄西林/舒巴坦、头孢唑林、头孢替坦、头孢曲松、头孢他啶、哌拉西林/他唑巴坦、复方新诺明、头孢吡肟、氨曲南、庆大霉素、厄他培南、亚胺培南、妥布霉素、阿米卡星、环丙沙星、呋喃妥因、左氧氟沙星18种常用抗生素的进行试验。
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。利用试管二倍稀释法将抗生素、菌液及TSB液体培养基加入96孔培养板中过夜培养，利用酶标仪测定抗生素对雷氏普罗威登斯菌的最小抑菌浓度(MIC)。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。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#雷氏普罗威登斯菌对17种抗生素耐药(1种敏感)，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.人源雷氏普罗威登斯菌的药敏试验MIC结果
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，以标准菌株(ATCC-31052，对头孢氨苄、头孢来星、卡那霉素、头孢菌素、庆大霉素、新霉素、四环素等抗生素敏感)作为参考，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2000μg/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雷氏普罗威登斯菌的最小抑菌浓度(MIC)，并将MIC浓度的前一个药物稀释浓度下的培养液转接至无菌的TSA固体培养基中继续培养24h，观察有无单菌落生成，如果无，则此浓度为木犀草素对多重耐药雷氏普罗威登斯菌的最低杀菌浓度(MBC)，实验结果见表3。
表3.木犀草素对多重耐药雷氏普罗威登斯菌的抑制结果
由表3可知，木犀草素对耐氨苄西林、氨苄西林/舒巴坦、头孢唑林、头孢替坦、头孢曲松、头孢他啶、妥布霉素、哌拉西林/他唑巴坦、环丙沙星、左氧氟沙星、阿米卡星、复方新诺明、头孢吡肟、厄他培南、亚胺培南、氨曲南及庆大霉素的雷氏普罗威登斯菌的抑制作用较好，其MIC为125μg/mL，MBC为250μg/mL。结果表明木犀草素不仅对雷氏普罗威登斯菌参考菌株ATCC-31052有抑菌作用，对本发明中的多重耐药雷氏普罗威登斯菌(例如，1#菌株)也有抑菌作用。
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雷氏普罗威登斯菌发挥抑制作用，能够有效缓解或解决多重耐药雷氏普罗威登斯菌的感染问题，降低病死率，为研究临床分离的雷氏普罗威登斯菌的抑菌剂提供科学依据，为开发抑制多重耐药雷氏普罗威登斯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雷氏普罗威登斯菌生长中的应用。
2.根据权利要求1所述的应用，其特征在于：所述多重耐药雷氏普罗威登斯菌为人源雷氏普罗威登斯菌。
3.根据权利要求1所述的应用，其特征在于：所述雷氏普罗威登斯菌的耐药性是通过微量二倍稀释法确定的。
4.根据权利要求1所述的应用，其特征在于：所述多重耐药雷氏普罗威登斯菌耐受的抗生素选自氨苄西林、氨苄西林/舒巴坦、头孢唑林、头孢替坦、头孢曲松、头孢他啶、哌拉西林/他唑巴坦、复方新诺明、头孢吡肟、氨曲南、庆大霉素、厄他培南、亚胺培南、妥布霉素、阿米卡星、环丙沙星、呋喃妥因、左氧氟沙星中的多种。
5.根据权利要求1所述的应用，其特征在于：所述多重耐药雷氏普罗威登斯菌选自耐氨苄西林、氨苄西林/舒巴坦、头孢唑林、头孢替坦、头孢曲松、头孢他啶、妥布霉素、哌拉西林/他唑巴坦、环丙沙星、左氧氟沙星、阿米卡星、复方新诺明、头孢吡肟、厄他培南、亚胺培南、氨曲南及庆大霉素的雷氏普罗威登斯菌。
6.根据权利要求4所述的应用，其特征在于：所述木犀草素对多重耐药雷氏普罗威登斯菌的最低杀菌浓度为30～250μg/mL，最小抑菌浓度为15～125μg/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雷氏普罗威登斯菌具有体外杀灭作用，以及抑制多重耐药雷氏普罗威登斯菌的体外生长。
8.木犀草素在制备抗多重耐药雷氏普罗威登斯菌的药物中的应用。
9.根据权利要求8所述的应用，其特征在于：所述多重耐药雷氏普罗威登斯菌为人源雷氏普罗威登斯菌。
10.根据权利要求8所述的应用，其特征在于：所述多重耐药雷氏普罗威登斯菌选自对氨苄西林、氨苄西林/舒巴坦、头孢唑林、头孢替坦、头孢曲松、头孢他啶、哌拉西林/他唑巴坦、复方新诺明、头孢吡肟、氨曲南、庆大霉素、厄他培南、亚胺培南、妥布霉素、阿米卡星、环丙沙星、呋喃妥因、左氧氟沙星中多种抗生素耐药的雷氏普罗威登斯菌。
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