微生物学报

Characteristic	DSM 15617	A128
Hydrolysis of
Arginine*	-	-
Aesculin*	+	+
Starch*	+	+
Activity of
Pyrrolidonylarylamidase*	-	-
α-galactosidase*	-	-
β-glucuronidase*	-	-
β-galactosidase*	-	-
Alkaline phosphatase*	-	-
Leucine arylamidase*	+	+
Growth in/at
6.5% NaCl	-	-
pH 9.6	+	+
45 ℃	+	+
Fermentation of
Ribose*	-	-
l-arabinose*	-	-
Mannitol*	-	-
Sorbitol*	-	-
Lactose*	+	+
Trehalose*	+	+
Inulin*	+	-
Raffinose*	+	+
Glycogen*	+	+
Amygdalin*	+	+

Characteristic	DSM 15617	A128
Hydrolysis of
Arginine*	-	-
Aesculin*	+	+
Starch*	+	+
Activity of
Pyrrolidonylarylamidase*	-	-
α-galactosidase*	-	-
β-glucuronidase*	-	-
β-galactosidase*	-	-
Alkaline phosphatase*	-	-
Leucine arylamidase*	+	+
Growth in/at
6.5% NaCl	-	-
pH 9.6	+	+
45 ℃	+	+
Fermentation of
Ribose*	-	-
l-arabinose*	-	-
Mannitol*	-	-
Sorbitol*	-	-
Lactose*	+	+
Trehalose*	+	+
Inulin*	+	-
Raffinose*	+	+
Glycogen*	+	+
Amygdalin*	+	+

药物种类 Types of drugs	抗生素 Antibiotic	MIC (µg/mL)	药敏判读结果 Drug susceptibility	耐药判读折点 Antibiotic resistance
Penicillins	Penicillin G	4	R	≤0.12	0.25-2	≥4
	Ampicillin	≤0.25	S	≤0.25	0.5-4	≥8
	Amoxicillin	≤0.25
Cephalosporins	Cefepime	1	S	≤1	2	≥4
	Cefotaxime	1	S	≤1	2	≥4
	Ceftriaxone	0.5	S	≤1	2	≥4
Carbapenem	Meropenem	0.125	S	≤0.5
Fluoroquinolone	Levofloxacin	1	S	≤2	4	≥8
	Moxifloxacin	0.125
Macrolide	Erythromycin	>8	R	≤0.25	0.5	≥1
Lincosamides	Clindamycin	>1	R	≤0.25	0.5	≥1
Amphenicols	Chloramphenicol	4	S	≤4	8	≥16
Glycopeptides	Vancomycin	0.5	S	≤1
	Teicoplanin	≤0.12
Tetracyclines	Tetracycline	2	S	≤2	4	≥8
	Tigecycline	≤0.06
Sulfonamide	TMP-SMX^*	>2/38	R			>2/38
Oxazolidinones	Linezolid	4	NS	≤2

药物种类 Types of drugs	抗生素 Antibiotic	MIC (µg/mL)	药敏判读结果 Drug susceptibility	耐药判读折点 Antibiotic resistance
Penicillins	Penicillin G	4	R	≤0.12	0.25-2	≥4
	Ampicillin	≤0.25	S	≤0.25	0.5-4	≥8
	Amoxicillin	≤0.25
Cephalosporins	Cefepime	1	S	≤1	2	≥4
	Cefotaxime	1	S	≤1	2	≥4
	Ceftriaxone	0.5	S	≤1	2	≥4
Carbapenem	Meropenem	0.125	S	≤0.5
Fluoroquinolone	Levofloxacin	1	S	≤2	4	≥8
	Moxifloxacin	0.125
Macrolide	Erythromycin	>8	R	≤0.25	0.5	≥1
Lincosamides	Clindamycin	>1	R	≤0.25	0.5	≥1
Amphenicols	Chloramphenicol	4	S	≤4	8	≥16
Glycopeptides	Vancomycin	0.5	S	≤1
	Teicoplanin	≤0.12
Tetracyclines	Tetracycline	2	S	≤2	4	≥8
	Tigecycline	≤0.06
Sulfonamide	TMP-SMX^*	>2/38	R			>2/38
Oxazolidinones	Linezolid	4	NS	≤2

我国首例携带 ermB 与 optrA 基因的青霉素耐药鼠口腔链球菌特征分析

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邰浩文 ¹ , 张嘉铭 ¹ , 郑翰 ¹ , 刘雨清 ¹^,² , 张静宜 ¹ , 付慧强 ¹ , 张艺凡 ¹ , 李娟 ¹^,^*

微生物学报 | 研究报告 2026,66(3): 1311-1325

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微生物学报 | 研究报告 2026, 66(3): 1311-1325

我国首例携带 ermB 与 optrA 基因的青霉素耐药鼠口腔链球菌特征分析

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邰浩文¹, 张嘉铭¹, 郑翰¹, 刘雨清¹^,², 张静宜¹, 付慧强¹, 张艺凡¹, 李娟¹^,^*

作者信息

^1.中国疾病预防控制中心传染病预防控制所，传染病溯源预警与智能决策全国重点实验室，北京

^2.中国医学科学院/北京协和医学院病原生物学研究所，北京

Characterization of the first penicillin-resistant Streptococcus orisratti strain carrying both ermB and optrA in China

Haowen TAI¹, Jiaming ZHANG¹, Han ZHENG¹, Yuqing LIU¹^,², Jingyi ZHANG¹, Huiqiang FU¹, Yifan ZHANG¹, Juan LI¹^,^*

Affiliations

^1.National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China

^2.National Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

出版时间: 2026-03-04 doi: 10.13343/j.cnki.wsxb.20250787

文章导航

摘要

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目的对一株分离自病死仔猪扁桃体、具有多重耐药表型的链球菌进行生物学表征及基因组分析以揭示其表型和基因型特征。方法取病死仔猪扁桃体组织研磨液接种于链球菌增菌培养基进行增菌培养；将增菌液接种至哥伦比亚血琼脂培养基进行链球菌分离培养。运用基质辅助激光解吸电离飞行时间质谱(MALDI-TOF MS)、生化鉴定系统及16S rRNA基因测序进行种属鉴定；通过稀释法测定最低抑菌浓度(minimum inhibitory concentrations, MIC)；利用Illumina二代测序平台完成全基因组测序；借助ResFinder平台分析耐药基因，并通过多序列比对分析青霉素结合蛋白(penicillin-binding proteins)基因的变异情况。结果经16S rRNA基因系统发育分析，该分离株鉴定为鼠口腔链球菌(Streptococcus orisratti)。药敏试验显示，该菌株对青霉素G、红霉素、克林霉素、甲氧苄啶-磺胺甲噁唑耐药，对利奈唑胺不敏感。基因组分析显示，该菌株携带大环内酯类和林可酰胺类耐药基因ermB以及恶唑烷酮类耐药基因optrA，且其青霉素结合蛋白编码基因多位点发生突变。结论本研究首次报道了一株同时携带ermB与optrA基因且对青霉素耐药的鼠口腔链球菌，揭示了猪源链球菌菌株具备获得多重耐药基因的能力，应关注动物源链球菌的耐药性和传播风险。

关键词

鼠口腔链球菌 / 多重耐药 / 耐药机制 / ermB / optrA

Abstract

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Objective To perform biological characterization and genomic analysis for a multidrug-resistant Streptococcus strain isolated from the tonsils of a dead piglet, thus elucidating its phenotypic and genotypic characteristics. Methods The tonsillar tissue homogenate from the dead piglet was inoculated into the Streptococcus enrichment medium for enrichment culture. The enriched culture was then streaked onto Columbia blood agar medium for Streptococcus isolation. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), a biochemical identification system, and 16S rRNA gene sequencing were employed for strain identification. The minimum inhibitory concentrations (MICs) were determined by the broth microdilution method. Whole-genome sequencing was conducted via the Illumina platform. The ResFinder database was used to analyze the resistance genes, and mutations in the genes encoding penicillin-binding proteins (PBPs) were investigated through multiple sequence alignment. Results The phylogenetic analysis based on 16S rRNA gene sequences identified the isolate as Streptococcus orisratti. Antimicrobial susceptibility testing revealed that the strain was resistant to penicillin G, erythromycin, clindamycin, and compound sulfamethoxazole, and it exhibited reduced susceptibility to linezolid. Whole-genome analysis identified the presence of the macrolide and lincoamide resistance gene ermB and the oxazolidinone resistance gene optrA. Furthermore, multiple mutations were detected in the genes encoding PBPs. Conclusion This study reports the first isolate of S. orisratti harboring both ermB and optrA and exhibiting resistance to penicillin. It highlights the capacity of porcine-derived streptococcal strains to acquire multidrug resistance genes, underscoring the need for increased vigilance regarding the resistance traits and transmission risks of animal-derived streptococci.

Key words

Streptococcus orisratti / multidrug resistance / resistance mechanisms / ermB / optrA

引用本文

邰浩文, 张嘉铭, 郑翰, 刘雨清, 张静宜, 付慧强, 张艺凡, 李娟. 我国首例携带 ermB 与 optrA 基因的青霉素耐药鼠口腔链球菌特征分析. 微生物学报, 2026 , 66 (3) : 1311 -1325 . DOI: 10.13343/j.cnki.wsxb.20250787

Haowen TAI, Jiaming ZHANG, Han ZHENG, Yuqing LIU, Jingyi ZHANG, Huiqiang FU, Yifan ZHANG, Juan LI. Characterization of the first penicillin-resistant Streptococcus orisratti strain carrying both ermB and optrA in China[J]. Acta Microbiologica Sinica, 2026 , 66 (3) : 1311 -1325 . DOI: 10.13343/j.cnki.wsxb.20250787

正文

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鼠口腔链球菌(Streptococcus orisratti)是一种革兰氏阳性球菌，隶属于厚壁菌界(Bacillati)芽孢杆菌门(Bacillota)乳酸菌纲(Bacilli)乳杆菌目(Lactobacillales)链球菌科(Streptococcaceae)链球菌属(Streptococcus)。该菌种于2000年由Zhu等^[1]从实验室SD大鼠下臼齿表面分离获得并命名。2005年，Hill等^[2]基于16S rRNA和cpn 60基因序列的系统发育分析，建议将猪链球菌(Streptococcus suis) 32和34血清型也归入该种，但该分类观点迄今尚未得到官方权威认证。目前，关于鼠口腔链球菌的研究报道十分有限，NCBI数据库中仅收录11株基因组序列，其中10株具备完整背景信息，模式菌株DSM 15617分离自鼠口腔，8株分离自家猪，1株分离自猫。

甲基转移酶(erythromycin ribosome methylation, Erm)基因家族在20世纪80年代被首次报道^[3-4]，其介导的甲基化修饰可介导对大环内酯类、林可酰胺类及链阳菌素B交叉耐药(macrolide-lincosamide streptogramin B resistance, MLSB)^[5]，主要包括ermA、ermB、ermC、ermF等基因亚型^[6]。其中，ermB基因编码红霉素核糖体甲基化酶，介导细菌的23S rRNA亚基的腺嘌呤N6位点甲基化^[7]。该基因已在多种链球菌中检出^[8]，如无乳链球菌(Streptococcus agalactiae)^[9-10]、肺炎链球菌(Streptococcus pneumoniae)^[11]和酿脓链球菌(Streptococcus pyogenes)等^[12]。在耐药基因的水平转移方面，移动遗传元件(mobile genetic elements, MGEs)，特别是整合和共轭元件(integrative and conjugative elements, ICEs)介导的ermB基因的获得被认为是大环内酯耐药链球菌菌株快速传播的主要原因^[13]。

恶唑烷酮类抗菌药物利奈唑胺于2000年被美国食品药品监督管理局(Food and Drug Administration, FDA)批准用于治疗耐甲氧西林金黄色葡萄球菌(methicillin-resistant Staphylococcus aureus, MRSA)、多重耐药肺炎链球菌(multidrug- resistant Streptococcus pneumoniae, MDR-SP)或耐万古霉素屎肠球菌(vancomycin resistant Enterococcus faecalis, VREF)引起的感染，是治疗革兰氏阳性多重耐药菌感染的关键药物之一^[14]。2015年，Wang等^[15]在肠球菌中鉴定出新型可转移恶唑烷酮耐药基因optrA，属ABC-F蛋白基因家族，可通过核糖体保护机制介导对多种临床相关抗生素的耐药^[16]。在肠球菌中optrA基因的水平转移主要通过质粒进行^[17-18]。除肠球菌外，NCBI数据库显示optrA基因也可见于空肠弯曲杆菌(Campylobacter jejuni)，在链球菌中比较少见，仅在猪链球菌(Streptococcus suis)^[19]、副猪链球菌(Streptococcus parasuis)^[20]和马链球菌(Streptococcus equi)^[21]等部分链球菌中有少量报道。在猪链球菌中optrA基因的传播主要通过横向基因转移方式实现^[19]。Dai等^[22]证明，猪链球菌中利奈唑胺的耐药性快速增加与携带多种optrA基因的MGEs有关。

链球菌对β-内酰胺类药物的耐药通常由青霉素结合蛋白(penicillin-binding proteins, PBP)基因突变介导^[23]。据CARSS监测网报道，我国肺炎链球菌对青霉素的耐药率约为1%^[24]。在肺炎链球菌中对青霉素的敏感性降低，需PBP2x和PBP2b同时突变^[25]。青霉素和头孢菌素的高水平耐药性还需PBP1a发生额外的突变^[25-26]。van der Linden等^[27]发现肺炎链球菌PBP2x基因存在多种链球菌基因序列转移的可能。近年也有研究报道在猪链球菌中出现青霉素耐药株^[28-30]。在猪链球菌PBP中，氨基酸替代主要发生在PBP2x和PBP2b^[28,31]。无乳链球菌和酿脓链球菌中也有分离获得了青霉素不敏感菌株的报道^[32-34]。

本研究首次报道一株同时对大环内酯类抗生素及青霉素耐药，并对利奈唑胺不敏感的链球菌通过对其表型特征和基因型特征的分析，阐述其生物学特征和耐药机制，旨在为掌握链球菌的耐药特征和耐药机制提供数据。

1 材料与方法

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1.1 材料

1.1.1 主要试剂和仪器

脱纤维羊血，天津市北辰区科技园区三牧畜技术有限公司；哥伦比亚血琼脂基础培养基，维百奥(北京)生物科技有限公司；革兰氏染色液，珠海贝索生物技术有限公司；质谱样本预处理试剂，郑州安图生物工程股份有限公司；API 50 CH碳水化合物鉴定试剂条、API酶活性科研试剂条(ZYM)、链球菌药敏卡片，梅里埃诊断产品(上海)有限公司；链球菌鉴定/药敏板条，碧迪医疗器械(上海)有限公司；Wizard^® Genomic DNA Purification Kit，Promega公司。

全自动平板分装仪，Systec GmbH公司；光学显微镜，Echo公司；基质辅助激光解吸电离飞行时间质谱，郑州安图生物工程股份有限公司；临界点干燥仪，Tousimis公司；喷金仪、扫描电镜，日立高新技术公司；全自动微生物鉴定药敏分析仪，梅里埃诊断产品(上海)有限公司；全自动微生物鉴定药敏分析仪，碧迪医疗器械(上海)有限公司。

1.1.2 培养基

哥伦比亚血琼脂培养基：哥伦比亚血琼脂基础培养基39.0 g/L，121 ℃灭菌20 min，冷却至48 ℃，按体积分数5%加入脱纤维绵羊血，充分混匀后制备琼脂平板。

改良胰蛋白胨大豆肉汤培养基(modified tryptone soybean broth, mTSB)：胰蛋白胨大豆肉汤培养基(tryptone soybean broth, TSB) 30.0 g/L，121 ℃灭菌20 min，冷却至室温，每升TSB中添加10.0 mL多黏菌素B水溶液(1.0 g/L)及10.0 mL萘啶酮酸的0.05 mol/L氢氧化钠溶液(1.0 g/L)。

1.2 菌株分离培养

2024年11月，对中国广西百色某养猪场死亡的仔猪进行表面消毒，无菌操作采集扁桃体样品，研磨后接种于mTSB液体培养基中，37 ℃、5% CO₂条件下培养16-18 h。使用10 μL一次性接种环进行三区划线，接种于含5%绵羊血的哥伦比亚血琼脂平板，37 ℃、5% CO₂培养24 h。挑取单菌落，在新鲜血平板上进行三区划线分离，经传代纯化后获得纯培养菌株。

1.3 菌株鉴定

采用基质辅助激光解吸电离飞行时间质谱和全自动微生物鉴定药敏分析仪进行初步细菌种属鉴定。使用临界点干燥仪对菌株进行干燥处理，之后使用喷金仪对干燥后的菌株进行喷金，最后使用扫描电镜拍摄菌株。使用API 50 CH和API酶活性科研试剂条检测菌株代谢特征。同时，使用Wizard^® Genomic DNA Purification Kit提取菌株基因组DNA，参考文献[35]设计16S rRNA基因引物，参考文献[1]完成16S rRNA基因扩增并测序。从NCBI数据库下载32种链球菌标准菌株16S rRNA基因序列，利用SILVA在线工具(https://www.arb-silva.de/)进行序列比对^[36]，采用MEGA 12.0.11软件构建系统发育树(邻接法，bootstrap=1 000)^[37]，进行种属鉴定。使用EZBioCloud在线网站(http://www.ezbiocloud.net/tools/an)计算分离菌株与模式株的平均核苷酸一致性(average nucleotide identity, ANI)^[38]，对分离菌株与模式株进行DNA (基因组)在线杂交(https://tygs.dsmz.de/)以验证种属鉴定的准确性^[39]。使用CD-HIT软件提取核心基因组^[40]，使用FastTree软件绘制系统发育树^[41]，使用iTOL在线网站进行可视化^[42]。

1.4 药物敏感性试验

以肺炎链球菌ATCC 49619为质控菌株，使用碧迪医疗器械(上海)有限公司的商业链球菌药敏板条和梅里埃公司的链球菌药敏卡片，通过肉汤微量稀释法测定抗菌药物青霉素G、美罗培南、红霉素、克林霉素、四环素、头孢噻肟、莫西沙星、氯霉素、替考拉宁、甲氧苄啶-磺胺甲噁唑、利奈唑胺等的最低抑菌浓度(minimum inhibitory concentration, MIC)，同时自配药敏板，使用琼脂稀释法对青霉素G的药物敏感性进行复核。参照CLSI M100 Ed35^[43]文件对结果进行判读。

1.5 核酸提取及全基因组分析

使用Wizard^® Genomic DNA Purification Kit提取菌株基因组DNA。采用Illumina NovaSeq PE 150平台(Illumina公司，https://www.illumina.com)进行全基因组测序。通过Rast网站(https://rast.nmpdr.org/rast.cgi)对全基因组序列进行功能注释^[44]。使用ICEfinder (https://tool2mml.sjtu.edu.cn/ICEberg3/ICEfinder.php)分析菌株中的可移动作用遗传元件^[45]。采用ResFinder 4.7.2 (http://genepi.food.dtu.dk/resfinder)鉴定耐药基因^[46]，使用Easyfig_2.2.5绘制耐药基因侧翼序列线性图^[47]。

从NCBI数据库下载全部鼠口腔链球菌基因组序列，经质量评估后筛选出10株用于后续分析。同时，下载与鼠口腔链球菌高度同源且PBP结构明确的猪链球菌PBP1a、PBP1b、PBP2a、PBP2b、PBP2x及PBP3氨基酸序列作为参考序列，进行多序列比对及突变位点分析。

2 结果与分析

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2.1 分离培养与鉴定

分离得到优势菌株A128，其为革兰氏阳性球菌，37 ℃、5% CO₂条件下培养24 h菌落呈圆形、光滑、湿润、边缘整齐，具体培养与形态特征详见图1。质谱鉴定结果为豕链球菌(Streptococcus porcinus)，全自动微生物鉴定分析仪鉴定为唾液链球菌(Streptococcus salivarius)。16S rRNA基因测序获得1 337 bp序列。通过与32种链球菌模式菌株16S rRNA基因比较构建系统发育树，16S rRNA基因系统发育树及全基因组核心基因系统发育分析显示该菌株与鼠口腔链球菌亲缘关系最近(图2、图3)。BLAST比对显示，其与模式菌株DSM 15617的16S rRNA基因一致性为97.54% (1 308/1 341)，存在7个位点的缺失，但与分离自澳大利亚犬类动物的鼠口腔链球菌9-70MP的16S rRNA基因一致性为98.80%，序列覆盖度为100.00%。菌株A128代谢特征与模式菌株DSM 15617基本一致(表1)。菌株A128全基因组序列存储于国家微生物科学数据中心(http://nmdc.cn)，编号为NMDC60215640。A128菌株与模式株平均核苷酸一致性为97.82%，ANI值大于96.00%可判定为同一个细菌种，dDDH结果为83.1%，DDH值大于70.0%可判定为同一个细菌种。综合评估上述结果，认定该菌株A128为鼠口腔链球菌。

2.2 药敏实验结果

药敏结果参照CLSI M100 Ed35中草绿色链球菌群(Streptococcus viridans group)的折点进行判读(利奈唑胺及甲氧苄啶-磺胺甲噁唑参考EUCAST标准)。如表2所示，菌株A128对青霉素G、红霉素、克林霉素和甲氧苄啶-磺胺甲噁唑耐药；对利奈唑胺不敏感；对氨苄西林、头孢吡肟、头孢噻肟、头孢曲松、左氧氟沙星、氯霉素、万古霉素、四环素敏感。

2.3 基因组测序结果

菌株A128基因组全长为2 371 027 bp，G+C含量为38.45%。共预测到2 406个蛋白质编码基因，其中包括618个假设蛋白和1 788个功能蛋白。功能蛋白中包含54个移动元件相关蛋白及16个噬菌体蛋白。此外，鉴定出59个tRNA基因和5个rRNA基因。

2.4 耐药基因分析

ResFinder 4.7.2耐药基因库比对分析显示，菌株A128携带4个耐药基因，分别为介导MLSB耐药的lsaE、lnuB和ermB基因，以及恶唑烷酮耐药基因optrA。

2.4.1 ermB 基因侧翼序列分析

A128菌株携带的ermB基因全长737 bp，与参考序列(NC_014959.1)相比存在3个位点的核苷酸突变(c.75T>C、c.515A>G、c.517G>A)，导致2个氨基酸替换(I75T、N222D)。无乳链球菌(CP021867.1、MW602970.1、OQ054582.1)和猪链球菌(MZ960465.1、CP032064.1)存在与A128菌株携带ermB基因突变位置一致的基因序列。如图4所示，携带ermB基因的contig长度为73 092 bp，其上、下游区域与猪链球菌1081基因组中的同源区高度相似，且同源区均含有噬菌体位点特异性酶等移动元件，非同源区域富含细菌代谢相关基因。

2.4.2 optrA 基因侧翼序列分析

A128携带的optrA基因全长为1 967 bp。与参考序列(NG_048023)高度同源，存在3处点突变(c.219G>A、c.626T>G、c.1541A>C)，导致3个氨基酸位点突变(G24D、Y160D、T465D)。本研究将获得的optrA基因与NCBI数据库中的序列进行BLAST比对。结果显示，未找到一致性为100%的序列。同源性最高的序列为粪肠球菌的optrA基因(MN731744.1)，该基因存在1个不同的点突变(c.219A>G)，携带此optrA基因的粪肠球菌对利奈唑胺耐药^[48]。

如图5所示，A128携带的optrA基因上游检测到整合酶基因，其所在区域与猪链球菌3372的一个携带整合酶的质粒序列高度同源；下游携带optrA基因的区域与粪肠球菌661质粒p661-b表现出高度同源性。

2.5 青霉素结合蛋白序列多态性分析

本研究基于从NCBI数据库中获取的10株鼠口腔链球菌全基因组序列，对其青霉素结合蛋白PBP1a、PBP1b、PBP2a和PBP2x的氨基酸序列进行了比较分析。结果显示，这些蛋白均存在多个氨基酸位点变异，其中PBP2a的变异程度最高，系统发育分析表明其序列多态性显著高于其他3种PBP蛋白。相反，PBP1b最为保守，所观察到的氨基酸替换位点数量最少。

2.5.1 PBP1a结构分析

PBP1a蛋白全长733个氨基酸，共发现20个高变位点。变异频率最高(100%)的氨基酸位点包括L409A/V、I286V和E704Q/H。另有7个高频发生替代的主要位点，分别为V39I、K248E、V345I、T374A、I411F、V498I和A572P，这些位点在80% (8/10)的菌株中均发生突变。此外，发现6个菌株特异性突变：SUG2382 (Y38F)、SUG2381 (K96R)、SRR11489755 (A589T)、SGI.063 (A648T，A717T)、SUG1074 (V718I)。

2.5.2 PBP1b结构分析

PBP1b蛋白由766个氨基酸组成，共包含17个高变区位点，是本研究中唯一未发现100%氨基酸替代的蛋白，表明其序列在进化上高度保守。主要高频变异位点为T566A、S567G和I572V (90%，9/10)；其次为Q332K、R371K和A372T (80%，8/10)。此外，鉴定出5个仅发生于单个菌株的低频氨基酸替代，分别位于以下菌株：A128中的T308N、SRR11489755中的A286T、SGI.245中的A381S、SRS10476997中的T394S与A616T。这些变异位点分散于不同菌株中，表明其可能属于随机突变事件。

2.5.3 PBP2a结构分析

PBP2a蛋白全长760个氨基酸，共鉴定出53个高变位点。其中，L20F与I24F为发生频率最高的突变位点，在所有菌株中均出现(100%，10/10)，其次为V28I和D724N (90%，9/10)。此外，共发现21个具备唯一性的氨基酸替代位点，这些变异集中分布于5个菌株：其中A128菌株中存在7个位点突变(M202V、W205G、S324A、I372N、P574S、D638N、A706T)；SGI.245菌株中有5个突变位点；SUG1074菌株中有4个；SRR11489755菌株中有3个；SGI.063菌株中有2个。

2.5.4 PBP2X结构分析

PBP2X蛋白全长为755个氨基酸，包含24个高变区位点。其中，F469L为发生频率最高的突变位点，出现在所有菌株中(100%，10/10)；其次为G8V、T626I和A630T，频率为90% (9/10)。此外，发现6个菌株特异性突变：SUG2382 (Y38F)、SUG2381 (K96R)、SRR11489755 (A589T)、SGI.063 (A648T，A717T)、SUG1074 (V718I)。

基于PBP氨基酸序列构建的系统发育树显示，不同PBP蛋白的进化关系存在差异，提示其可能经历独立的进化历程(图6)。

3 讨论与结论

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本研究中，质谱法鉴定结果(豕链球菌)、全自动微生物鉴定分析仪结果(唾液链球菌)与16S rRNA鉴定结果(鼠口腔链球菌)存在差异，提示商品化的质谱法和生化鉴定法在链球菌种属鉴定方面存在局限性^[49-50]。对于非常见链球菌菌株，结合16S rRNA基因测序乃至全基因组测序进行确认是确保鉴定准确性的必要策略。

本研究首次在鼠口腔链球菌中同时检出ermB和optrA基因，ermB基因的存在介导了菌株对红霉素和克林霉素的高水平耐药，该基因在酿脓链球菌、无乳链球菌、肺炎链球菌等链球菌各属菌株中普遍存在，已成为介导链球菌菌株对大环内酯类和克林霉素类耐药的最主要机制^[51-52]。

利奈唑胺是针对革兰阳性菌感染治疗的高级别药物，在链球菌中较少发现耐药情况。该菌株携带optrA基因，导致其对利奈唑胺的敏感性降低。基因环境分析显示，ermB和optrA基因侧翼均存在可移动遗传元件(如整合酶)，且optrA基因所在的contig与粪肠球菌661中质粒序列高度同源，推测optrA基因可能源自粪肠球菌661质粒基因。该发现为理解多重耐药基因在链球菌种间及属间的传播机制提供了重要线索。

青霉素耐药是链球菌耐药领域的重要问题。目前，青霉素作为链球菌感染治疗的一线用药^[51]，已在肺炎链球菌^[53]、猪链球菌^[28]等链球菌中出现耐药株。在酿脓链球菌^[34]和口腔链球菌(Streptococcus oralis)^[54]中也观察到敏感性下降。据我们所知，本研究为首次报道鼠口腔链球菌青霉素耐药株。

有研究表明，PBP多个活性位点的氨基酸替换是链球菌对β-内酰胺类药物敏感性降低的主要机制^[29]。在肺炎链球菌中，PBP2b和PBP2x同时存在是肺炎链球菌存活所必需的^[55-56]。肺炎链球菌对青霉素的耐药与PBP2b特定突变相关^[57-58]。然而，本研究未在鼠口腔链球菌中鉴定出PBP2b，仅发现PBP2x。在链球菌中，有研究证明头孢噻肟可诱导肺炎链球菌PBP2x突变^[59]，头孢类药物也可引起无乳链球菌PBP2x突变^[60-61]，而PBP2x突变与酿脓链球菌和肺炎链球菌对头孢噻肟耐药相关^[60,62]。由于菌株数量有限，目前鼠口腔链球菌尚无药物敏感、耐药折点以及流行病学界值折点。根据草绿色链球菌折点判断A128对头孢噻肟敏感，但其MIC值为1 μg/mL，远超肺炎链球菌的流行病学界值折点(ECV为0.060 μg/mL)、酿脓链球菌(ECV为0.030 μg/mL)和无乳链球菌(ECV为0.125 μg/mL)，提示A128菌株中PBP2x的氨基酸替换可能是其对头孢噻肟敏感性下降的分子机制。

综上所述，本研究从病死仔猪扁桃体中分离出一株同时携带ermB和optrA基因且青霉素耐药的鼠口腔链球菌，揭示了猪源链球菌菌株具备获得多重耐药基因的能力，应关注动物源链球菌的耐药特征和传播风险。

基金

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国家疾病预防控制局高层次公共卫生人才培养支持项目
广州国家实验室专项项目(GZNL2024A01025)

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2026年第66卷第3期

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doi: 10.13343/j.cnki.wsxb.20250787

接收时间：2025-10-21
首发时间：2026-03-12
出版时间：2026-03-04

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出版历史

收稿日期：2025-10-21
录用日期：2025-12-23

基金

Public Health Talent Support Project of National Disease Control and Prevention Administration

国家疾病预防控制局高层次公共卫生人才培养支持项目

Major Project of Guangzhou National Laboratory(GZNL2024A01025)

广州国家实验室专项项目(GZNL2024A01025)

作者信息

^1.中国疾病预防控制中心传染病预防控制所，传染病溯源预警与智能决策全国重点实验室，北京

^2.中国医学科学院/北京协和医学院病原生物学研究所，北京

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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Characteristic	DSM 15617	A128
Hydrolysis of
Arginine*	-	-
Aesculin*	+	+
Starch*	+	+
Activity of
Pyrrolidonylarylamidase*	-	-
α-galactosidase*	-	-
β-glucuronidase*	-	-
β-galactosidase*	-	-
Alkaline phosphatase*	-	-
Leucine arylamidase*	+	+
Growth in/at
6.5% NaCl	-	-
pH 9.6	+	+
45 ℃	+	+
Fermentation of
Ribose*	-	-
l-arabinose*	-	-
Mannitol*	-	-
Sorbitol*	-	-
Lactose*	+	+
Trehalose*	+	+
Inulin*	+	-
Raffinose*	+	+
Glycogen*	+	+
Amygdalin*	+	+

Characteristic

DSM 15617

A128

Hydrolysis of

Arginine*

Aesculin*

Starch*

Activity of

Pyrrolidonylarylamidase*

α-galactosidase*

β-glucuronidase*

β-galactosidase*

Alkaline phosphatase*

Leucine arylamidase*

Growth in/at

6.5% NaCl

pH 9.6

45 ℃

Fermentation of

Ribose*

l-arabinose*

Mannitol*

Sorbitol*

Lactose*

Trehalose*

Inulin*

Raffinose*

Glycogen*

Amygdalin*

药物种类 Types of drugs	抗生素 Antibiotic	MIC (µg/mL)	药敏判读结果 Drug susceptibility	耐药判读折点 Antibiotic resistance
Penicillins	Penicillin G	4	R	≤0.12	0.25-2	≥4
	Ampicillin	≤0.25	S	≤0.25	0.5-4	≥8
	Amoxicillin	≤0.25
Cephalosporins	Cefepime	1	S	≤1	2	≥4
	Cefotaxime	1	S	≤1	2	≥4
	Ceftriaxone	0.5	S	≤1	2	≥4
Carbapenem	Meropenem	0.125	S	≤0.5
Fluoroquinolone	Levofloxacin	1	S	≤2	4	≥8
	Moxifloxacin	0.125
Macrolide	Erythromycin	>8	R	≤0.25	0.5	≥1
Lincosamides	Clindamycin	>1	R	≤0.25	0.5	≥1
Amphenicols	Chloramphenicol	4	S	≤4	8	≥16
Glycopeptides	Vancomycin	0.5	S	≤1
	Teicoplanin	≤0.12
Tetracyclines	Tetracycline	2	S	≤2	4	≥8
	Tigecycline	≤0.06
Sulfonamide	TMP-SMX^*	>2/38	R			>2/38
Oxazolidinones	Linezolid	4	NS	≤2

药物种类

Types of drugs

抗生素

Antibiotic

MIC (µg/mL)

药敏判读结果

Drug susceptibility

耐药判读折点

Antibiotic resistance

Penicillins

Penicillin G

≤0.12

0.25-2

≥4

Ampicillin

≤0.25

0.5-4

≥8

Amoxicillin

≤0.25

Cephalosporins

Cefepime

≤1

≥4

Cefotaxime

≤1

≥4

Ceftriaxone

0.5

≤1

≥4

Carbapenem

Meropenem

0.125

≤0.5

Fluoroquinolone

Levofloxacin

≤2

≥8

Moxifloxacin

0.125

Macrolide

Erythromycin

≤0.25

0.5

≥1

Lincosamides

Clindamycin

≤0.25

0.5

≥1

Amphenicols

Chloramphenicol

≤4

≥16

Glycopeptides

Vancomycin

0.5

≤1

Teicoplanin

≤0.12

Tetracyclines

Tetracycline

≤2

≥8

Tigecycline

≤0.06

Sulfonamide

TMP-SMX^*

>2/38

Oxazolidinones

Linezolid

≤2