产超广谱β内酰胺酶和碳青霉烯酶肺炎克雷伯菌替加环素耐药性机制的初步分析

doi:10.11843/j.issn.0366-6964.2025.07.042

摘要/Abstract

摘要：

耐碳青霉烯类肺炎克雷伯菌(carbapenem resistant Klebsiella pneumoniae，CRKP)的报道逐年增多，替加环素已成为治疗耐碳青霉烯类肺炎克雷伯菌感染的最后一道防线，本研究旨在对3株耐碳青霉烯类肺炎克雷伯菌的替加环素耐药性机制进行初步研究。采用微量肉汤稀释法测定对替加环素的敏感性并评估外排泵抑制剂(PAβN)对耐药性的影响；结合前期全基因组测序结果，采用PCR验证与替加环素耐药相关基因及其调控因子、孔蛋白相关基因的转录[acrAB-tolC、oqxAB、msbA、kexD、kdeA、kpnEF、kpnGH、Ompk37、OmpA、ramA、ramR、marA、rarA、acrR、tet(X4)、tetA]，通过实时荧光定量PCR检测耐药菌株和敏感菌株之间的基因转录水平差异。结果显示：体外药敏试验发现3株肺炎克雷伯菌KP30535、KP30845和KP30727分别对替加环素耐药、中介、敏感。外源添加PAβN增加了菌株对替加环素的敏感性。实时荧光定量PCR结果表明，耐药菌株(KP30535)和中介菌株(KP30845)中acrAB、kpnGH、ramA转录水平显著(P < 0.05)高于对照菌ATCC13883，KP30535中kpnE转录水平显著(P < 0.01)高于对照菌；KP30727中acrB、ramA、ramR转录水平显著(P < 0.05)高于对照菌；3株菌中孔蛋白Ompk37、OmpA转录水平极显著(P < 0.001)低于对照菌。Spearman相关性分析表明，acrAB、kpnGH和kexD和孔蛋白OmpA与菌株替加环素耐药表型相关($|r|$ ≥0.6)。综上，acrAB、kpnGH、kexD和孔蛋白OmpA的差异表达是影响本研究中耐碳青霉烯类肺炎克雷伯菌对替加环素耐药性的重要因素，为后续更深入地研究提供参考依据。

关键词: 肺炎克雷伯菌, 替加环素, 耐药机制, 外排泵, 孔蛋白, 调控因子

Abstract:

The reports of carbapenem-resistant Klebsiella pneumoniae (CRKP) are increasing annually, and tigecycline has become the last line of defense for treating carbapenem-resistant Klebsiella pneumoniae (CRKP) infections, this article presents a preliminary study on the mechanism of tigecycline resistance in three strains of carbapenem-resistant Klebsiella pneumoniae. Broth microdilution method was used to determine the sensitivity of CRKP to tigecycline and evaluate the effect of efflux pump inhibitor, PAβN, on drug resistance. Combined with the results of the previous whole genome sequencing, polymerase chain reaction (PCR) testing was employed to validate the presence of genes and corresponding regulatory factors, porins (acrAB-tolC, oqxAB, msbA, kexD, kdeA, kpnEF, kpnGH, Ompk37, OmpA, ramA, ramR, marA, rarA, acrR, tet(X4), tetA) associated with tigecycline resistance, and differences in gene expression levels between resistant and sensitive strains were detected by real-time fluorescence quantitative PCR. In vitro drug susceptibility experiments showed that the three CRKP strains KP30535, KP30845 and KP30727 were resistant, intermediate and sensitive to tigecycline respectively. In vivo addition of PAβN increased the resistance of strain to tigecycline. The results of real-time quantitative fluorescence PCR showed that the transcription levels of acrAB, kpnGH and ramA in resistant strain KP30535 and intermediate strain KP30845 were significantly higher (P < 0.05) than those of the control strain ATCC13883, and the transcription level of kpnE in KP30535 was extremely higher (P < 0.01). The transcription levels of acrB, ramA and ramR in KP30727 were significantly higher (P < 0.05) than control. The transcription of porins Ompk37 and OmpA in the three strains were markedly lower (P < 0.001) than control. The results of Spearman correlation analysis showed that acrAB, kpnGH, kexD and the porin OmpA were associated with the antimicrobial resistance phenotype of the strain to tigecycline ($|r|$ ≥0.6). The preliminary research results indicate that the different expression of acrAB, kpnGH, kexD, and porin OmpA may be important factors affecting the resistance of CRKP to tigecycline in this study, which can provide reference for further in-depth research.

Key words: Klebsiella pneumoniae, tigecycline, resistance mechanism, efflux pump, porins, expression regulators

中图分类号:

R978

韦钰诗, 孙文, 庞晓敏, 王玉莲. 产超广谱β内酰胺酶和碳青霉烯酶肺炎克雷伯菌替加环素耐药性机制的初步分析[J]. 畜牧兽医学报, 2025, 56(7): 3507-3518.

WEI Yushi, SUN Wen, PANG Xiaomin, WANG Yulian. A Preliminary Study on the Mechanism of Tigecycline Resistance in ESBLs- and Carbapenemase-Producing Klebsiella pneumoniae[J]. Acta Veterinaria et Zootechnica Sinica, 2025, 56(7): 3507-3518.

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菌种编号 Strains number	种属来源 Species origin	分离地区 Isolated area	分离时间 Isolated time	序列类型 ST types	登录号 Accession number
KP30727	人	武汉大学中南医院	2021-12-17	ST15	SAMN43221293
KP30535	人	武汉大学中南医院	2021-12-17	ST11	SAMN43221298
KP30845	人	武汉大学中南医院	2021-12-17	ST11	SAMN43221295

抗菌药物 Antibiotic	判定标准 Judgment criteria			浓度 Concentration	质控范围 Quality control	参考文献 Reference
抗菌药物 Antibiotic	敏感 Sensitive	中介 Intermediate	耐药 Resistance	浓度 Concentration	质控范围 Quality control	参考文献 Reference
替加环素 Tigecycline	≤2	4	≥8	0.03~16.00	0.03~0.25	FDA，2016

引物名称 Primer name	引物序列(5′→3′) Sequences	产物/bp Products	参考文献 References
rpoB-F	AGGCGAATCCAGCTTGTTCAGC	147	^[19]
rpoB-R	TGACGTTGCATGTTCGCACCCATCA	147	^[19]
acrA-F	ATGTGACGATAAACCGGCTC	101	^[20]
acrA-R	CTGGCAGTTCGGTGGTTATT	101	^[20]
acrB-F	CGATAACCTGATGTACATGTCC	207	^[21]
acrB-R	CCGACAACCATCAGGAAGCT	207	^[21]
tolC-F	CTACAAACAGGCGGTGGTCT	170	^[22]
tolC-R	TGTTCAGCTCGTTGATCAGG	170	^[22]
oqxA-F	GACAGCGTCGCACAGAATG	850	^[23]
oqxA-R	GATCAGCGTGGCTTTGAACT	850	^[23]
oqxB-F	CGAAGAAAGACCTCCCTACCC	538
oqxB-R	GAACCCTGACCCAGTCCTAAA	538
tet(X4)-F	ATGGAAACCGGCTAATGGCT	195	^[24]
tet(X4)-R	TGTAGCGTTCGTCCCAATCG	195	^[24]
tetA-F	GCTACATCCTGCTTGCCTTC	210	^[25]
tetA-R	CATAGATCGCCGTGAAGAGG	210	^[25]
ramA-F	ATTTCCGCTCAGGTGATT	115	^[26]
ramA-R	GTTGCAGATGCCATTTCG	115	^[26]
ramR-F	CGCGCAATATCTGGAACAGC	292	^[27]
ramR-R	TCAAAGCCGAGGGCGATAAT	292	^[27]
rarA-F	ATTGCCCTCGGCTTTGAC	102
rarA-R	AACAGAGCGGCTGATACTCC	102
marA-F	GGAGATTGCGCAGAAGCTCA	157	^[28]
marA-R	GGATTCGCCAGGTACATTCG	157	^[28]
acrR-F	TGACAGCGAACCATTCGACA	126	本研究 This study
acrR-R	CATGTTCAGCAATCCGCTCG	126	本研究 This study
msbA-F	GGATCGCTCAGTGCTGCTAT	157
msbA-R	CATACCCATCATGTGGCCGA	157
kpnG-F	AAGGCTAAGACCCAACTGGC	244
kpnG-R	TGGCGTTGTACTGCTGGATT	244
kpnH-F	AACGCGCAGCAGATATACGA	276
kpnH-R	GCGAGAACTGGACAACCTGA	276
kdeA-F	GTTGTTCCCGTTATGTCTGGTGC	170	^[29]
kdeA-R	CCAGCAGCCACTGTAAAAACATGC	170	^[29]
kexD-F	ACCGGTTGCGCAATACCCTGA	184
kexD-R	CGTAATTGACGCCATCCCTG	184
kpnE-F	ATTGCTGAAATTACCGGCAC	172	^[29]
kpnE-R	AAATACCGATCCCTTCCCAC	172	^[29]
kpnF-F	ACAATGGCGATTGCCAGCCA	96	本研究 This study
kpnF-R	AAGTCCGGCACCCAGAAAAA	96	本研究 This study
Ompk37-F	CAACAACACCGAGACCTCCA	171	^[30]
Ompk37-R	GCATAGGTGTAGGAGTCGCC	171	^[30]
OmpA-F	AGACCGTTTAGCCAGGTTCG	208	本研究 This study
OmpA-R	GTCACGGCTGGTATCTACGG	208	本研究 This study

菌株 Stains	替加环素 TGC		替加环素+PAβN TGC+PAβN		MIC变化 MIC changes
菌株 Stains	MIC/(μg·mL^-1)	结果判定Judgment	MIC/(μg·mL^-1)	结果判定Judgment	MIC变化 MIC changes
ATCC13883	0.5	敏感	0.25	敏感	2
KP30845	4.0	中介	2.00	敏感	2
KP30535	8.0	耐药	2.00	敏感	4
KP30727	2.0	敏感	0.50	敏感	4

菌株 Strains	基因区域 Gene region	一致性/% Identity	突变 Mutation	核苷酸变化 Nucleotide change	耐药表型 Phenotype
KP30727	Ompk37	99.73	p.I70M	ATT>ATG	carbapenem
			p.I128M	ATT>ATG	carbapenem
	acrR	98.46	p.P161R	CCC>CGG	fluorquinolone
			p.G164A	GGC>GCC	fluorquinolone
			p.F172S	TTC>TCC	fluorquinolone
			p.R173G	CGA>GGG	fluorquinolone
			p.L195V	CTC>GTC	fluorquinolone
			p.F197I	TTT>ATT	fluorquinolone
P30727	acrR	98.46	p.K201M	AAG>ATG	fluorquinolone
	ramR	99.15	p.A19V	GCG>GTG	tigecycline
KP30535	Ompk37	99.50	p.I70M	ATT>ATG	carbapenem
			p.I128M	ATT>ATG	carbapenem
			p.N230G	AAC>GGC	carbapenem
			p.M233Q-Frameshift	undefined	carbapenem
	acrR	100.00	p.P161R	CGG>CGG	fluoroquinolone
			p.G164A	GGC>GCC	fluoroquinolone
			p.F172S	TTC>TCC	fluoroquinolone
			p.R173G	CGA>GGG	fluoroquinolone
		97.33	p.L195V	CTC>GTC	fluoroquinolone
			p.F197I	TTT>ATT	fluoroquinolone
			p.K201M	AAG>ATG	fluoroquinolone
KP30845	Ompk37	99.50	p.I70M	ATT>ATG	carbapenem
			p.I128M	ATT>ATG	carbapenem
			p.N230G	AAC>GGC	carbapenem
		100.00	p.M233Q-Frameshift	undefined	carbapenem
	acrR		p.P161R	CGG>CGG	fluoroquinolone
KP30845	acrR	100.00	p.G164A	GGC>GCC	fluoroquinolone
			p.F172S	TTC>TCC	fluoroquinolone
			p.R173G	CGA>GGG	fluoroquinolone
		97.33	p.L195V	CTC>GTC	fluoroquinolone
			p.F197I	TTT>ATT	fluoroquinolone
			p.K201M	AAG>ATG	fluoroquinolone