鲍曼不动杆菌在环境美罗培南浓度变化时耐药性的改变及其机制

doi:10.3969/j.issn.1674-8115.2023.11.007

上海交通大学学报（医学版） ›› 2023, Vol. 43 ›› Issue (11): 1396-1407.doi: 10.3969/j.issn.1674-8115.2023.11.007

• 论著 · 基础研究 • 上一篇

鲍曼不动杆菌在环境美罗培南浓度变化时耐药性的改变及其机制

赵富茂¹(), 彭玫¹, 彭晓露¹, 舒韦韦², 彭丽¹()

^1.重庆医科大学附属第一医院呼吸与危重症医学科，重庆 400016
^2.重庆医科大学附属永川医院重症医学科，重庆 402160

收稿日期:2023-02-28 接受日期:2023-09-19 出版日期:2023-11-28 发布日期:2023-11-28
通讯作者: 彭丽 E-mail:506884746@qq.com;pli1228@163.com
作者简介:赵富茂（1995—），女，硕士生；电子信箱：506884746@qq.com。
基金资助:
重庆市卫生健康委员会医学科研计划项目(2017ZDXM004);重庆市社会事业与民生保障科技创新专项项目(cstc2017shmsA130031)

Changes in drug resistance of Acinetobacter baumannii during the change of meropenem concentration in the environment and its mechanism

ZHAO Fumao¹(), PENG Mei¹, PENG Xiaolu¹, SHU Weiwei², PENG Li¹()

^1.Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
^2.Department of Critical Care Medicine, Yongchuan Hospital of Chongqing Medical University, Chongqing 402160, China

Received:2023-02-28 Accepted:2023-09-19 Online:2023-11-28 Published:2023-11-28
Contact: PENG Li E-mail:506884746@qq.com;pli1228@163.com
Supported by:
Medical Research Program of Chongqing Municipal Health Commission(2017ZDXM004);Chongqing Special Project for Scientific and Technological Innovation of Social Undertakings and People′s Livelihood Security(cstc2017shmsA130031)

摘要/Abstract

摘要：

目的·探寻鲍曼不动杆菌（Acinetobacter baumannii）在环境中碳青霉烯类药物美罗培南浓度改变时耐药性变化的机制。方法·通过改变鲍曼不动杆菌标准敏感株ATCC19606和临床耐药株AB.2014培养环境中的美罗培南浓度等条件，诱导对美罗培南不同耐药程度的衍生株。测量所得菌株的生长曲线，并提取各菌株的DNA和RNA，采用PCR分析菌株耐药性改变后的碳青霉烯酶基因IMI、KPC、GES-1、IMP、VIM、NDM-1、OXA23、OXA24、OXA51、OXA58的表达情况；通过实时荧光定量PCR（real-time fluorescent quantitative PCR，RT-qPCR）分析不同耐药程度的鲍曼不动杆菌耐药基因，包括OXA51，外排泵基因adeB、adeG、adeJ，孔蛋白基因carO、omp33-36、oprC，青霉素结合蛋白基因ponA的表达水平变化；通过全基因组测序及生物信息学工具分析耐药性改变后菌株的差异基因富集情况的变化。结果·获得了鲍曼不动杆菌ATCC19606与AB.2014对美罗培南不同耐药程度的11个衍生株，最低抑菌浓度（minimum inhibitory concentration，MIC）为1~128 μg/mL。ATCC19606及其衍生株的生长速度和峰值随着耐药性的增加而降低，但AB.2014及其衍生株并没有表现出这种趋势。ATCC19606及其衍生株表达3个碳青霉烯酶基因OXA51、VIM和IMP，AB.2014及其多数衍生株表达4个碳青霉烯酶基因OXA23、OXA51、VIM和IMP，仅AB.2014的一个复敏衍生株出现了OXA23丢失。RT-qPCR结果显示，仅在ATCC19606及其耐药衍生株中oprC基因的表达量随着耐药性的升高而降低，多数耐药基因的表达水平与菌株的耐药水平变化一致。生物信息学分析提示ATCC19606不同衍生株之间的差异基因主要富集于铁载体摄取跨膜转运体活性、细胞外膜、细菌分泌系统和群体感应等，而AB.2014不同衍生株之间的差异基因主要富集于细胞外膜、细胞对化学刺激的反应、阿特拉津降解和RNA聚合酶等。结论·碳青霉烯类药物环境压力会引起鲍曼不动杆菌耐药性发生变化，碳青霉烯酶、外排泵、孔蛋白、青霉素结合蛋白多种基因可能同时参与了菌株耐药性的变化；碳青霉烯酶OXA23丢失可能导致耐药鲍曼不动杆菌对碳青霉烯类药物复敏。

关键词: 鲍曼不动杆菌, 美罗培南, 耐药性, 碳青霉烯酶, 外排泵, 孔蛋白, 青霉素结合蛋白

Abstract:

Objective ·To explore the mechanism of changes in resistance to meropenem (MEM), a carbapenem drug, in Acinetobacter baumannii (A. baumannii) cultured in different antibiotic concentrations. Methods ·Through changing the MEM concentration and other culture conditions of the standard sensitive strain of A. baumannii ATCC19606 and the clinical drug-resistant strain AB.2014, the derived strains with different levels of MEM-resistance were induced. The growth curves of all the stains were detected. DNA and RNA of them were extracted. PCR was used to analyze the expression of carbapenemase genes, including IMI, KPC, GES-1, IMP, VIM, NDM-1, OXA23, OXA24, OXA51, and OXA58. Real-time fluorescent quantitative PCR (RT-qPCR) was used to analyze the expression levels of the carbapenemase gene (OXA51), efflux pump genes (adeB, adeG, and adeJ), pore protein genes (carO, omp33-36, and oprC)and the penicillin-binding protein gene (ponA)in the A. baumannii strains with different resistance to MEM, of which the differential gene enrichment was also detected by whole genome sequencing and bioinformatics tools. Results ·The 11 derived strains of ATCC19606 and AB.2014 with different levels of resistance to MEM were obtained, of which the minimum inhibitory concentrations (MIC) were 1?128 μg/mL. The growth rates and peak values of ATCC19606 and its derivatives decreased with the increase of drug resistance, but AB.2014 and its derivatives did not show this trend. ATCC19606 and its derived strains expressed 3 carbapenemase genes, i.e., OXA51, VIM and IMP, while AB.2014 and most of its derived strains expressed 4 carbapenemase genes, i.e., OXA23, OXA51, VIM and IMP, with only one sensitized derivative of AB.2014 losing OXA23 gene. RT-qPCR results showed that only in ATCC19606 and its drug-resistant derivatives, the expression level of oprC gene decreased with the increase of drug resistance, and the expression levels of most drug-resistant genes were consistent with the changes of drug resistance levels of the strains. Bioinformatics analysis indicated that the differential genes among different ATCC19606 strains were mainly enriched in the siderophore uptake transmembrane transporter activity, cell outer membrane, bacterial secretion system and quorum sensing, while those among AB.2014 strains were mainly enriched in cell outer membrane, cellular response to chemical stimulus, atrazine degradation and RNA polymerase. Conclusion ·The environmental pressure from carbapenems will cause the change of drug resistance of A. baumannii with the involvement of the genes of carbapenemases, efflux pumps, pore proteins and penicillin-binding proteins. The loss of carbapenemase gene OXA23 may lead to the desensitization of drug-resistant A. baumannii strains to carbapenems.

Key words: Acinetobacter baumannii, meropenem (MEM), drug resistance, carbapenemase, efflux pump, pore protein, penicillin-binding protein

中图分类号:

R378.99

赵富茂, 彭玫, 彭晓露, 舒韦韦, 彭丽. 鲍曼不动杆菌在环境美罗培南浓度变化时耐药性的改变及其机制[J]. 上海交通大学学报（医学版）, 2023, 43(11): 1396-1407.

ZHAO Fumao, PENG Mei, PENG Xiaolu, SHU Weiwei, PENG Li. Changes in drug resistance of Acinetobacter baumannii during the change of meropenem concentration in the environment and its mechanism[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2023, 43(11): 1396-1407.

图/表 8

表1 碳青霉烯酶基因PCR鉴定引物

Tab 1 Primers used in the identification of carbapenemase genes by PCR

Ambler class	Gene	Forward primer (5′→3′)	Reverse primer (5′→3′)	Fragment size/bp	Reference
A	IMI	ATAGCCATCCTTGTTTAGCTC	TCTGCGATTACTTTATCCTC	818	[12]
	KPC	GCTTCCCACTGTGCAGCTCATTCA	CGGTCGTGTTTCCCTTTAGCCAATC	456	－
	GES-1	ATGCGCTTCATTCACGCAC	CTATTTGTCCGTGCTAAGG	814	[13]
B	IMP	AGGCCAAGATCGTTTAGTCACTGT	GTGTTGTACAGATAGAACCAGGACCAA	461	－
	VIM	TGGTGAGTATCCGACAGTCAACGA	CGAATGCGCAGCACCAG	450	－
	NDM-1	AGGACAAGATGGGCGGTATGGACG	CCATGCGGGCCGTATGAGTGATT	429	－
D	OXA51	ATGAACATTAAAGCACTC	CTATAAAATACCTAATTGTTC	825	[11]
	OXA23	ACTTGCTATGTGGTTGCTTC	TGGAAGCTGTGTATGTGCTA	555	[14]
	OXA24	TTTGCCGATGACCTTGCACATAAC	TCATGTTGAGCGAAAAGGGGATTTTT	208	－
	OXA58	CGATCAGAATGTTCAAGCGC	TCCCCTCTGCGCTCTACATACA	666	－

表2 RT-qPCR引物

Tab 2 Primers used in RT-qPCR analysis

Gene	Forward primer (5′→3′)	Reverse primer (5′→3′)	Reference
16S rRNA	GTAGCTTGCTACTGGACCTAG	CATACTCTAGCTCACCAGTATCG	[15]
OXA51	GATTTAGCTCGTCGTATTGGA	AAGCGTTTTATTAGCTAGCTTG	[16]
adeB	GGAATAAGGCACCACAACAAT	CGAAGTTAGGAATACCAGCAATAC	－
adeG	TCACCAGATAATCGCTATG	GACTTCACCTACACCTTG	－
adeJ	CCTATTGCACAATATCCAACGA	AGGATAAGTCGCAGCAATCG	[17]
oprC	ACTCGATACAAAGCGGTGGA	TTTAATACGTGAACCAAACATACCTC	[17]
carO	TGTTCATGACAGCTATGCATTCGATA	CCCAATGCTAAACCTACATATGGGT	[17]
omp33-36	GCAACTTACAACCACACTGA	TAACAACATAGCACCAACTTCTAA	－
ponA	GTCAGCCAGGTTCTACCATCAA	CCATCAGAGTTCTTCGGTGTCC	－

表3 ATCC19606、AB.2014及它们衍生株对MEM的MIC值

Tab 3 MIC values of ATCC19606， AB.2014 and their derivative strains to MEM

Strain	MIC/(μg·mL^－1)
ATCC19606	1
ATCC19606-R1	8
ATCC19606-R2	16
ATCC19606-R3	128
ATCC19606-R3-S1	64
ATCC19606-R3-S2	1
AB.2014	16
AB.2014-R1	64
AB.2014-R2	128
AB.2014-S1	8
AB.2014-S2	2
AB.2014-R1-S1	16
AB.2014-R1-S2	8

图1 不同耐药性鲍曼不动杆菌菌株的生长曲线Note： A. Growth curves of the strains with increased MEM-resistance. B. Growth curves of the strains with decreased MEM-resistance.

Fig 1 Growth curves of A. baumannii strains with different drug resistance

图2 不同耐药性鲍曼不动杆菌菌株中 OXA23 基因的PCR鉴定Note： A. Detection of OXA23 gene expression in ATCC19606 and its MEM-resistant variants. B.Detection of OXA23 gene expression in AB.2014 and its MEM-resistant variants. C.Detection of OXA23 gene expression in MEM-sensitive variants.

Fig 2 Analysis of OXA23 gene expression in A. baumannii strains with different drug resistance by PCR

图3 RT-qPCR检测不同耐药性鲍曼不动杆菌菌株中抗MEM相关基因的表达Note： A. Expression profiles of the genes in ATCC19606 and its MEM-resistant variants. B. Expression profiles of the genes in AB.2014 and its MEM-resistant variants. C. Expression profiles of the genes in ATCC19606-R3 and its MEM-sensitive variants. D. Expression profiles of the genes in AB.2014 and its MEM-sensitive variants. E. Expression profiles of the genes of AB.2014-R1 and its MEM-sensitive variants. ①P=0.005, ②P= 0.003, ③P=0.000, ④P=0.007, ⑤P=0.001, ⑥P=0.002, ⑦P=0.006.

Fig 3 RT-qPCR analysis of MEM-resistance-related genes in A. baumannii strains with different drug resistance

图4 ATCC19606、AB.2014及它们衍生株之间差异基因的GO分析Note： A. Enrichment of differential genes in ATCC19606 compared with ATCC19606-R3. B. Enrichment of differential genes in ATCC19606-R3-S2 compared with ATCC19606-R3. C. Enrichment of differential genes in AB.2014 compared with AB.2014-R3. D. Enrichment of differential genes in AB.2014-R3 compared with AB.2014. E. Enrichment of differential genes in AB.2014 compared with AB.2014-S2. F. Enrichment of differential genes in AB.2014-S2 compared with AB.2014. G. Enrichment of differential genes in ATCC19606 compared with AB.2014. H. Enrichment of differential genes in AB.2014 compared with ATCC19606.

Fig 4 GO analysis of differential genes among ATCC19606, AB.2014 and their derivatives

图5 ATCC19606、AB.2014及它们衍生株之间差异基因的KEGG分析Note： A. Enrichment of differential genes in ATCC19606 compared with ATCC19606-R3. B. Enrichment of differential genes in ATCC19606-R3 compared with ATCC19606. C. Enrichment of differential genes in ATCC19606-R3 compared with ATCC19606-R3-S2. D. Enrichment of differential genes in AB.2014 compared with AB.2014-R3. E. Enrichment of differential genes in AB.2014 compared with AB.2014-S2. F. Enrichment of differential genes in AB.2014-R2-S2 compared with AB.2014-R2.

Fig 5 KEGG analysis of differential genes among ATCC19606, AB.2014 and their derivatives

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鲍曼不动杆菌在环境美罗培南浓度变化时耐药性的改变及其机制

Changes in drug resistance of Acinetobacter baumannii during the change of meropenem concentration in the environment and its mechanism

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