生牛乳中金黄色葡萄球菌异质性耐药及机制研究

doi:10.11843/j.issn.0366-6964.2025.04.040

畜牧兽医学报 ›› 2025, Vol. 56 ›› Issue (4): 1934-1946.doi: 10.11843/j.issn.0366-6964.2025.04.040

生牛乳中金黄色葡萄球菌异质性耐药及机制研究

和晓兰¹(), 赵艳坤¹^,², 孟璐¹, 刘慧敏¹, 高姣姣², 郑楠¹^,*()

1. 中国农业科学院北京畜牧兽医研究所, 北京 100193
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重点实验室, 乌鲁木齐 830091

收稿日期:2024-03-14 出版日期:2025-04-23 发布日期:2025-04-28
通讯作者: 郑楠 E-mail:2460213483@qq.com;zhengnan@caas.cn
作者简介:和晓兰(2001-), 女, 河北内丘人, 硕士生, 主要从事乳品微生物学研究, E-mail: 2460213483@qq.com
基金资助:
国家重点研发计划(2022YFD1301000)；国家现代农业产业技术体系(CARS36)；农产品质量安全风险评估(GJFP20220304)；中国农业科学院科技创新工程(ASTIP-IAS12)；天山创新团队(2022D14016)；新疆奶产业技术体系专项经费资助(XJARS-11)

Investigation of Heteroresistance and Its Mechanism of Staphylococcus aureus in Raw Milk

HE Xiaolan¹(), ZHAO Yankun¹^,², MENG Lu¹, LIU Huimin¹, GAO Jiaojiao², ZHENG Nan¹^,*()

1. Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
2. Key Laboratory of Agro-Products Quality and Safety of Xinjiang, Ministry of Agriculture and Rural Affairs-Laboratory of Quality and Safety Risk Assessment for Agro-Products, Institute of Quality Standards & Testing Technology for Agro-Products, Xinjiang Academy of Agricultural Sciences, Urumqi 830091, China

Received:2024-03-14 Online:2025-04-23 Published:2025-04-28
Contact: ZHENG Nan E-mail:2460213483@qq.com;zhengnan@caas.cn

摘要/Abstract

摘要：

旨在了解生牛乳中分离的金黄色葡萄球菌耐药情况以及金黄色葡萄球菌的异质性耐药流行情况，并探究异质性耐药机制。从东北、华北、华东、华南、西北和西南六个地区采集179批次生牛乳，分离鉴定出金黄色葡萄球菌36株。采用肉汤微量稀释法鉴定金黄色葡萄球菌的敏感性和耐药性，联合纸片扩散法和E-test法从抗菌药物敏感表型的菌株中筛选疑似异质性耐药菌株，利用菌群谱型分析法(PAP)进行确证，传代测定异质性耐药稳定性，通过全基因组和比较基因组学分析异质性耐药机制。结果表明，36株金黄色葡萄球菌对β-内酰胺类抗生素耐药率达11.11%~61.11%，对四环素和氨基糖苷类抗生素表现高度敏感。初筛得到19种金黄色葡萄球菌和抗菌药物组合异质性耐药，确证3种组合为异质性耐药表型，其中仅金黄色葡萄球菌J23保持稳定的异质性耐药表型。本研究表明，生牛乳源的金黄色葡萄球菌对β-内酰胺类和喹诺酮类抗菌药物耐药性较高，对阿莫西林/克拉维酸的异质性耐药机制与blaZ和金属β-内酰胺酶的表达有关，对四环类药物的异质性耐药与四环素外排泵表达和耐药蛋白有关。

关键词: 生牛乳, 金黄色葡萄球菌, 异质性耐药, 耐药亚群, 全基因组学

Abstract:

This experiment was conducted to study the drug resistances of Staphylococcus aureus isolated from raw milk, the prevalence of heteroresistance of Staphylococcus aureus and explore the mechanism of heteroresistance. Thirty-six Staphylococcus aureus isolates were isolated from 179 batches of raw milk collected from Northeast, North China, East China, South China, Northwest and Southwest. The sensitivity and resistance of Staphylococcus aureus were identified using broth microdilution method. The combination of disk diffusion method and E-test method was used to screen suspected heteroresistant strains from strains with sensitive phenotypes, and then the suspected heteroresistant strains were confirmed by Population analysis profiling(PAP). The stability of the heteroresistant phenotype after serial passage was measured. Finally, whole-genome sequencing and whole genome re-sequencing analysis were used to determine the heteroresistant mechanisms. The results showed that 36 strains of Staphylococcus aureus were resistant to β-lactam antibiotics, the resistant rate to ranges from 11.11% to 61.11%, and had high sensitivity to tetracycline and aminoglycoside antibiotics. 19 combinations of Staphylococcus aureus and antibiotics with heteroresistant were identified through initial screening, and it was confirmed that the 3 combinations exhibited heteroresistant phenotypes, of which only amoxicillin-clavulanate-J23 heteroresistant stabled after serial passage. This study demonstrates that S. aureus of raw milk origin is high resistant to β-lactam and quinolone antimicrobials. Heteroresistant mechanisms to amoxicillin-clavulanic acid are associated with blaZ and metal β-lactamase expression. Heteroresistant mechanisms to tetracyclines is associated with tetracycline efflux pumps and resistance proteins.

Key words: raw milk, S. aureus, heteroresistant, resistant subpopulations, whole-genome sequencing

中图分类号:

S852.611

和晓兰, 赵艳坤, 孟璐, 刘慧敏, 高姣姣, 郑楠. 生牛乳中金黄色葡萄球菌异质性耐药及机制研究[J]. 畜牧兽医学报, 2025, 56(4): 1934-1946.

HE Xiaolan, ZHAO Yankun, MENG Lu, LIU Huimin, GAO Jiaojiao, ZHENG Nan. Investigation of Heteroresistance and Its Mechanism of Staphylococcus aureus in Raw Milk[J]. Acta Veterinaria et Zootechnica Sinica, 2025, 56(4): 1934-1946.

图/表 12

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序号No.	地理区域Geographical region	牧场地址Pasture address
1	东北地区	黑龙江省齐齐哈尔市克山县
2		黑龙江省齐齐哈尔市甘南县
3		吉林省白城市镇赉县
4	华北地区	内蒙古自治区呼和浩特市和林格尔县
5		内蒙古自治区呼和浩特市赛罕区
6		河北省张家口市塞北管理区
7		河北省保定市满城区
8		河北省保定市徐水区
9		天津市滨海新区
10		北京市昌平区
11	华东地区	山东省淄博市高青县
12		江苏省盐城市大丰区
13		浙江省杭州市建德市
14		福建省南平市延平区
15	华南地区	广东省清远市连州市
16		广东省湛江市遂溪县
17	西北地区	陕西省渭南市大荔县
18		甘肃省金昌市金川区
19		甘肃省嘉峪关市
20	西南地区	贵州省贵阳市修文县
21		云南省曲靖市陆良县
22		四川省达州市宣汉县

抗菌药物类别 Types of antibiotics	抗菌药物名称 Antibiotic	药敏类型 Types of drug resistance	菌株MIC/(μg·mL^-1) Strain MIC	菌株数 Strain number	比率 Rate
β-内酰胺类 β-Lactams	青霉素	S	0.125	18	50.00%
		I	/	0	0.00%
		R	0.25~32	18	50.00%
	氨苄西林	S	0.125	14	38.89%
		I	/	0	0.00%
		R	0.5~64	22	61.11%
	苯唑西林	S	0.25~2	28	77.78%
		I	/	0	0.00%
		R	4~128	8	22.22%
	阿莫西林/克拉维酸	S	0.25/0.12	14	38.89%
		I	0.5/0.25	9	25.00%
		R	1/0.5~16/8	13	36.11%
	头孢噻吩	S	0.25~1	29	80.56%
		I	4	1	2.78%
		R	16~128	6	16.67%
	头孢噻呋	S	0.25~2	32	88.89%
		I	/	0	0.00%
		R	16~128	4	11.11%
大环内酯类 Macrolide	红霉素	S	0.25~0.5	28	77.78%
		I	1	1	2.78%
		R	16~128	7	19.44%
林可霉素类 Lincosamides	克林霉素	S	0.125~0.25	30	83.33%
		I	1~2	3	8.33%
		R	4~64	3	8.33%
氨基糖苷类 Aminoglycoside	庆大霉素	S	0.25~2	34	94.44%
		I	8	2	5.56%
		R	/	0	0.00%
四环素类 Tetracycline	多西环素	S	0.25~4	33	91.67%
		I	8	1	2.78%
		R	16	2	5.56%
	四环素	S	0.25~2	31	86.11%
		I	8	1	2.78%
		R	32~64	4	11.11%
氯霉素类 Chloramphenicols	氟苯尼考	S	1~4	30	83.33%
		I	8	3	8.33%
		R	16~128	3	8.33%
喹诺酮类 Quinolones	环丙沙星	S	0.125~1	28	77.78%
		I	/	0	0.00%
		R	4~64	8	22.22%
磺胺类 Sulfonamides	复方新诺明	S	0.12/2.4~1/19	35	97.22%
		I	/	0	0.00%
		R	32/608	1	2.78%

菌株 Strain	疑似异质性耐药抗菌药物 Antimicrobial agents with suspected heteroresistance
J6	克林霉素、庆大霉素
J16	苯唑西林
J23	阿莫西林/克拉维酸
J26	苯唑西林

菌株 Strain	疑似异质性耐药抗菌药物 Antimicrobial agents with suspected heteroresistance
J6	克林霉素、庆大霉素、阿莫西林/克拉维酸、环丙沙星、复方新诺明
J16	苯唑西林、多西环素
J19	复方新诺明、四环素、庆大霉素
J22	克林霉素、多西环素、四环素、复方新诺明
J23	阿莫西林/克拉维酸、复方新诺明
J26	苯唑西林、克林霉素、多西环素

抗菌药物-菌株 Antimicrobial-Strain	初始MIC值/(μg·mL^－1) Initial MIC	菌株类型 Strain type	异质性耐药亚群发生频率 Frequency of heteroresistant subpopulation
阿莫西林克拉维酸-J23 Amoxicillin Clavulanic Acid-J23	0.25/0.12	Heteroresistance	3.26×10^-7
四环素-J22 Tetracycline-J22	0.25	Heteroresistance	9.41×10^-6
多西环素-J22 Doxycycline-J22	0.25	Heteroresistance	1.69×10^-7

生牛乳中金黄色葡萄球菌异质性耐药及机制研究

Investigation of Heteroresistance and Its Mechanism of Staphylococcus aureus in Raw Milk

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抗菌药物-菌株 Antimicrobial-Strain	第1代MIC MIC of the first passage	第15代MIC MIC of the 15th passage
阿莫西林克拉维酸J23 Amoxicillin Clavulanic Acid-J23	2/1(R)	2/1(R)
四环素J22 Tetracycline-J22	1(S)	2(S)
多西环素J22 Doxycycline-J22	0.25(S)	0.25(S)

基因 Gene	同义突变 Synonymous	非同义突变 Nonsynonymous	插入 Insertion	缺失 Deletion
J2GL000299	11	3	0	0
J2GL000618	14	0	0	0
J2GL000650	14	2	0	0
J2GL001192	51	17	7	7
J2GL001826	15	4	0	1

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基因 Gene	同义突变 Synonymous	非同义突变 Nonsynonymous	插入 Insertion	缺失 Deletion
J2GL000296	28	14	4	5
J2GL000464	6	1	0	0
J2GL000585	23	1	0	0
J2GL000597	0	0	0	0
J2GL001006	4	1
J2GL001140	15	4	0	0
J2GL001141	15	3	0	0
J2GL001382	2	1	0	0
J2GL001394	0	0	0	0
J2GL001383	5	3	0	0
J2GL001384	5		0	0
J2GL001385	7	7	0	0
J2GL001386	27	10	1	1