奶源异质性耐药大肠杆菌及其耐药亚群特性研究

doi:10.11843/j.issn.0366-6964.2024.12.043

畜牧兽医学报 ›› 2024, Vol. 55 ›› Issue (12): 5813-5824.doi: 10.11843/j.issn.0366-6964.2024.12.043

奶源异质性耐药大肠杆菌及其耐药亚群特性研究

高姣姣¹^,²(), 郑楠³, 邵伟¹, 陈贺², 马宪兰², 赵艳坤¹^,²^,³^,*()

1. 新疆农业大学动物科学学院新疆肉乳用草食动物营养实验室, 乌鲁木齐 830052
2. 新疆农业科学院农业质量标准与检测技术研究所农业农村部农产品质量安全风险评估实验室(乌鲁木齐)新疆农产品质量安全实验室, 乌鲁木齐 830091
3. 中国农业科学院北京畜牧兽医研究所农业农村部奶及奶制品质量安全控制重点实验室, 北京 100193

收稿日期:2024-06-04 出版日期:2024-12-23 发布日期:2024-12-27
通讯作者: 赵艳坤 E-mail:2816996289@qq.com;yankunzhao90@163.com
作者简介:高姣姣(1999-), 女, 陕西榆林人, 硕士生, 主要从事乳品病原微生物研究, E-mail: 2816996289@qq.com
基金资助:
自治区天山英才项目(2023TSYCCX0034);国家自然科学基金(32060797);自治区重大科技专项资助项目(2022A02006-3-2)

Characterization of Heterogeneous Drug-resistant Escherichia coli and Its Drug-resistant Subpopulations from Milk Sources

GAO Jiaojiao¹^,²(), ZHENG Nan³, SHAO Wei¹, CHEN He², MA Xianlan², ZHAO Yankun¹^,²^,³^,*()

1. Xinjiang Meat and Milk Herbivore Nutrition Laboratory, College of Animal Science, Xinjiang Agricultural University, Urumqi 830052, China
2. Ministry of Agriculture and Rural Affairs Laboratory of Quality and Safety Risk Assessment for Agro-Products, Key Laboratory of Agro-Products Quality and Safety of Xinjiang, Institute of Quality Standards & Testing Technology for Agro-Products, Xinjiang Academy of Agricultural Sciences, Urumqi 830091, China
3. Key Laboratory for Quality & Safety Control for Milk and Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China

Received:2024-06-04 Online:2024-12-23 Published:2024-12-27
Contact: ZHAO Yankun E-mail:2816996289@qq.com;yankunzhao90@163.com

摘要/Abstract

摘要：

旨在探究奶源大肠杆菌是否存在异质性耐药现象，对异质性耐药大肠杆菌及其耐药亚群的生物学特性进行研究，探究其可能的异质性耐药机制。本研究采用微量肉汤稀释法测定从生牛乳中分离得到的1株大肠杆菌D1的最低抑菌浓度(minimum inhibitory concentration，MIC)，采用K-B纸片扩散法对大肠杆菌的异质性耐药情况进行初筛，采用菌落谱型分析(population analysis profile，PAP)进行确证，并通过耐药稳定性测试和生物膜试验探究大肠杆菌的异质性耐药特征，最后通过全基因组测序和重测序分析产生异质性耐药的机制。结果发现，该株大肠杆菌对多黏菌素E表现为中介，对磺胺异恶唑耐药，对其余抗生素表现为敏感，K-B纸片扩散法筛出2种大肠杆菌-抗菌药物异质性耐药组合。PAP确证显示，D1-阿莫西林-克拉维酸的MIC/最高非抑菌浓度(maximum noninhibitory concentration，MNIC)的比值为8，耐药亚群的发生频率为2.45×10^-6，确证为多西环素异质性耐药菌株。传代稳定性表明耐药亚群不能稳定遗传，而生长试验不存在生长滞后现象，耐药亚群的生物膜产量极显著大于亲本菌株。全基因组测序结果发现，耐药亚群与亲本菌株之间存在基因突变，而突变基因txR是一种特定的转录调节因子，可能导致大肠杆菌对多西环素产生异质性耐药。奶源大肠杆菌存在多西环素异质性耐药的现象，提示临床中应合理使用多西环素抗生素，因此在使用多西环素进行临床治疗时应更加注意异质性耐药的发生，需采用有效的检测方法，为临床防控和合理使用抗生素提供指导。

关键词: 奶源大肠杆菌, 异质性耐药, 耐药亚群, 全基因组

Abstract:

The aim of this study was to investigate whether heteroresistance exists in milk-derived Escherichia coli, and to characterize the biology of heteroresistance E. coli and its resistant subgroups, in order to explore possible heteroresistance mechanisms.The minimum inhibitory concentration (MIC) of one E. coli strain named D1 which isolated from raw cow's milk was determined by micro broth dilution method. The heteroresistance of E. coli was initially screened by the K-B paper diffusion method, and confirmed by the population analysis profile (PAP), and the heteroresistance characteristics of E. coli were investigated by resistance stability test and biofilm assay, finally, the mechanism of heterogeneous resistance was analyzed by whole genome sequencing and resequencing. The results showed that this E. coli was intermediary to polymyxin E, resistant to sulfisoxazole, and showed sensitivity to the rest of the antibiotics, and two E. coli-antimicrobial heteroresistance combinations were screened out by K-B paper diffusion assay.PAP confirmation showed that the MIC/maximum noninhibitory concentration (MNIC) ratio of E. coli was 8, and the occurence frequency of the resistant subgroups was 2.45×10^-6, confirming D1 to be a heteroresistance doxycycline-resistant strain. The stability of transmission showed that the resistant subpopulation could not be inherited stably, while there was no growth lag in the growth test, and the biofilm production of the resistant subpopulation was significantly greater than that of the parental strain. Whole genome sequencing revealed that there was a gene mutation between the resistant subpopulation and the parental strain, and the mutant gene txR is a specific transcriptional regulator that may lead to heteroresistance to doxycycline in E. coli. In conclusion, the existence of heteroresistance to doxycycline in E. coli from milk sources suggests that doxycycline antibiotics should be used rationally in the clinic, therefore, more attention should be paid to the occurrence of heteroresistance when using doxycycline in clinical treatment, and effective detection methods need to be used to provide guidance for clinical prevention and control and rational use of antibiotics.

Key words: milk-derived Escherichia coli, heteroresistance, resistant subgroups, whole genome

中图分类号:

S852.612

高姣姣, 郑楠, 邵伟, 陈贺, 马宪兰, 赵艳坤. 奶源异质性耐药大肠杆菌及其耐药亚群特性研究[J]. 畜牧兽医学报, 2024, 55(12): 5813-5824.

GAO Jiaojiao, ZHENG Nan, SHAO Wei, CHEN He, MA Xianlan, ZHAO Yankun. Characterization of Heterogeneous Drug-resistant Escherichia coli and Its Drug-resistant Subpopulations from Milk Sources[J]. Acta Veterinaria et Zootechnica Sinica, 2024, 55(12): 5813-5824.

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抗菌药物 Antimicrobial	MIC折点/(μg·mL^-1) MIC folding point			D1菌株MIC/(μg·mL^-1) D1 Antimicrobial Strain MIC	药敏类型 Type of drug sensitivity
抗菌药物 Antimicrobial	S	I	R	D1菌株MIC/(μg·mL^-1) D1 Antimicrobial Strain MIC	药敏类型 Type of drug sensitivity
氨苄西林 Ampicillin	≤8	16	≥32	1	S
阿莫西林/克拉维酸 Amoxicillin/clavulanic acid	≤8/4	16/8	≥32/16	2/1	S
头孢噻吩 Cephalothin	-	-	-	8	-
头孢噻呋 Ceftiofur	≤2	4	≥8	≤0.25	S
美罗培南 Meropenem	≤1	2	≥4	≤0.25	S
链霉素 Straptomycin	-	-	-	4	-
卡那霉素 Kanamycin	≤16	32	≥64	4	S
庆大霉素 Gentamicin	≤4	8	≥16	0.5	S
四环素 Tetracycline	≤4	8	≥16	≤0.25	S
多西环素 Doxycycline	≤4	8	≥16	0.25	S
氟苯尼考 Florfenicol	≤4	8	≥16	4	S
多粘菌素 E Colistin	-	≤2	≥4	0.5	I
利福昔明 Rifaximin	-	-	-	4	-
环丙沙星 Ciprofloxacin	≤0.25	0.5	≥1	≤0.25	S
磺胺异恶唑 Sulfafurazole	≤256	-	≥512	1 024	R
复方新诺明 Sulfamethoxazole	≤2/38	-	≥4/76	≤0.12/2.4	S

抗生素种类 Antibiotic type	耐药基因 Drug-resistance gene
氨基香豆素抗菌药物 Aminocoumarin antibiotic	gyrB、tolC、baeR、baeS、mdtC、mdtB、mdtA、cpxA
膦酸抗菌药物 Phosphonic acid antibiotic	uhpA、uhpT、murA、ptsI、glpT、mdtG、cyaA
氟喹诺酮类抗菌药物 Fluoroquinolone antibiotic	gadX、mdtF、mdtE、CRP、acrF、acrE、acrS、tolC、parE、parC、emrB、emrA、emrR、evgS、evgA、gyrA、mipA、H-NS、mdtH、acrA、acrB、mdtM、soxR、lamB
大环内酯类抗菌药物 Macrolide antibiotic	gadX、mdtF、mdtE、CRP、tolC、evgS、evgA
头孢菌素 Cephamycin	acrF、acrE、acrS、tolC、marA、H-NS、ompF、acrA、acrB、EC-15、soxR、soxS
噁唑烷酮类抗菌药物 Oxazolidinone antibiotic	mlaF、mlaD
肽抗菌药物 Peptide antibiotic	bacA、pmrF、yojI、ugd、eptA
氨基糖苷类抗菌药物 Aminoglycoside antibiotic	tolC、acrD、baeR、baeS、mipA、kdpE、cpxA
四环素抗菌药物 Tetracycline antibiotic	tolC、evgS、evgA、emrK、emrY、mdfA、lamB
碳青霉烯类抗菌药物 Carbapenem antibiotic	tolC、marA、ompF、soxS
核苷类抗菌药物 Nucleoside antibiotic	leuO、mdtN、mdtO、mdtP

分类 type	耐药基因 drug-resistance gene
耐药结节分化家族(RND) Resistant Nodal Differentiation Family (RND)	acrA、acrB、acrD、acrE、acrF、acrR、acrS、baeR、baeS、cpxA、CRP、evgA、evgS、gadX、H-NS、marA、marR、mdtA、mdtB、mdtC、mdtE、mdtF、soxR、soxS、tolC
主要易化子超家族(MFS) Major facilitator superfamily (MFS)	emrA、emrB、emrK、emrR、emrY、evgA、evgS、H-NS、mdfA、mdtG、mdtH、mdtM、mdtN、mdtO、mdtP、leuO、soxR、soxS、tolC
ATP结合盒家族超家族(ABC) ATP-binding cassette family superfamily (ABC)	msbA、mlaD、mlaF、soxR、soxS、tolC、yojl

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奶源异质性耐药大肠杆菌及其耐药亚群特性研究

Characterization of Heterogeneous Drug-resistant Escherichia coli and Its Drug-resistant Subpopulations from Milk Sources

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