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已发表论文
blaIMP-45 基因扩增促进铜绿假单胞菌对亚胺培南的异质性耐药
Authors Du Y, Yuan M, Su Z, Liu Z, Qiu X, Xu S , Zhu X, Li Z
Received 8 June 2025
Accepted for publication 22 August 2025
Published 10 November 2025 Volume 2025:18 Pages 5863—5875
DOI https://doi.org/10.2147/IDR.S532962
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Dr Yan Li
Yiyao Du,1,2 Min Yuan,3 Zhedi Su,1,2 Zhiguo Liu,3 Xiaotong Qiu,3 Shuai Xu,3 Xiong Zhu,4 Zhenjun Li5
1Academy of Medical Sciences, Shanxi Medical University, Shanxi, People’s Republic of China; 2Department of Epidemiology, School of Public Health, Shanxi Medical University, Shanxi, People’s Republic of China; 3Chinese Center for Disease Control and Prevention, Institute of Infectious Disease Prevention and Control, Beijing, People’s Republic of China; 4Central and Clinical Laboratory of Sanya People’s Hospital, Sanya, Hainan, People’s Republic of China; 5Chinese Center for Disease Control and Prevention, Beijing, People’s Republic of China
Correspondence: Zhenjun Li, Chinese Center for Disease Control and Prevention, Beijing, People’s Republic of China, Email lizhenjun@icdc.cn
Objective: To investigate the contribution of blaIMP-45 and its plasmid-borne genetic context in the development of imipenem heteroresistance in Pseudomonas aeruginosa.
Methods: Six clinical isolates of P. aeruginosa (HN41, HN66, HN67, HN125, HN148, and HN232) were analyzed. Broth microdilution confirmed imipenem(IMP) resistance in all the strains (MIC ≥ 8 mg/L). Whole-genome sequencing was performed to identify the presence of blaIMP-45. E-test strips were used to indicate suspected heteroresistance phenotypes, while Population Analysis Profile (PAP) assays were conducted to definitively classify the strains. Complete plasmid sequencing of HN232 (IMP-HR) and HN41 (IMP-NHR) was performed to identify the genetic context of blaIMP-45. Pre-exposure of IMP-HR strain HN232 to sub-inhibitory IMP (1, 4, and 32 mg/L) for 24h was conducted to assess regrowth frequency. Quantitative reverse-transcription PCR (qRT-PCR) and digital PCR (ddPCR) were used to measure blaIMP-45 expression and gene copy number.
Results: Whole-genome sequencing revealed the absence of blaIMP-45 in the HN67 and HN125 strains. E-test strips indicated suspected heteroresistance phenotypes, while Population Analysis Profile (PAP) assays definitively classified HN66, HN148, and HN232 as heteroresistant (heteroresistant subpopulation inhibitory concentration, HIC/HNIC ratio ≥ 8), with their maximum permissive growth concentrations (256 mg/L) 32-fold higher than non-heteroresistant strains HN67 and HN125 (8 mg/L), implicating blaIMP-45 in driving phenotypic heterogeneity. Complete plasmid sequencing of HN232 (IMP-HR) and HN41 (IMP-NHR) identified blaIMP-45 within the In786 integron, embedded in the Tn 7445 transposon (a Tn 1403 derivative) on IncP-2 type plasmids. Notably, the blaIMP-45-flanking genetic environment was conserved between HR and NHR strains, excluding promoter region variations (eg, PcH2 and P2 promoters within In786) as drivers of differential expression. Pre-exposure of IMP-HR strain HN232 to sub-inhibitory IMP (1, 4, and 32 mg/L) for 24h induced dose-dependent increases in regrowth frequency at 4 and 8 mg/L IMP. Quantitative reverse-transcription PCR (qRT-PCR) and digital PCR (ddPCR) demonstrated that low-dose IMP exposure (1 mg/L, 24h) upregulated blaIMP-45 expression and increased the gene copy number in HN232, whereas the NHR strain HN41 exhibited stringent plasmid regulation.
Conclusion: The study provided critical insights into blaIMP-45-mediated IMP heteroresistance in P. aeruginosa, highlighting plasmid-encoded amplifiable resistance determinants as key modulators of phenotypic adaptability under antibiotic pressure.
Keywords: heteroresistance, carbapenem-resistant Pseudomonas aeruginosa, blaIMP-45, IncP-2 plasmid
1Academy of Medical Sciences, Shanxi Medical University, Shanxi, People’s Republic of China; 2Department of Epidemiology, School of Public Health, Shanxi Medical University, Shanxi, People’s Republic of China; 3Chinese Center for Disease Control and Prevention, Institute of Infectious Disease Prevention and Control, Beijing, People’s Republic of China; 4Central and Clinical Laboratory of Sanya People’s Hospital, Sanya, Hainan, People’s Republic of China; 5Chinese Center for Disease Control and Prevention, Beijing, People’s Republic of China
Correspondence: Zhenjun Li, Chinese Center for Disease Control and Prevention, Beijing, People’s Republic of China, Email lizhenjun@icdc.cn
Objective: To investigate the contribution of blaIMP-45 and its plasmid-borne genetic context in the development of imipenem heteroresistance in Pseudomonas aeruginosa.
Methods: Six clinical isolates of P. aeruginosa (HN41, HN66, HN67, HN125, HN148, and HN232) were analyzed. Broth microdilution confirmed imipenem(IMP) resistance in all the strains (MIC ≥ 8 mg/L). Whole-genome sequencing was performed to identify the presence of blaIMP-45. E-test strips were used to indicate suspected heteroresistance phenotypes, while Population Analysis Profile (PAP) assays were conducted to definitively classify the strains. Complete plasmid sequencing of HN232 (IMP-HR) and HN41 (IMP-NHR) was performed to identify the genetic context of blaIMP-45. Pre-exposure of IMP-HR strain HN232 to sub-inhibitory IMP (1, 4, and 32 mg/L) for 24h was conducted to assess regrowth frequency. Quantitative reverse-transcription PCR (qRT-PCR) and digital PCR (ddPCR) were used to measure blaIMP-45 expression and gene copy number.
Results: Whole-genome sequencing revealed the absence of blaIMP-45 in the HN67 and HN125 strains. E-test strips indicated suspected heteroresistance phenotypes, while Population Analysis Profile (PAP) assays definitively classified HN66, HN148, and HN232 as heteroresistant (heteroresistant subpopulation inhibitory concentration, HIC/HNIC ratio ≥ 8), with their maximum permissive growth concentrations (256 mg/L) 32-fold higher than non-heteroresistant strains HN67 and HN125 (8 mg/L), implicating blaIMP-45 in driving phenotypic heterogeneity. Complete plasmid sequencing of HN232 (IMP-HR) and HN41 (IMP-NHR) identified blaIMP-45 within the In786 integron, embedded in the Tn 7445 transposon (a Tn 1403 derivative) on IncP-2 type plasmids. Notably, the blaIMP-45-flanking genetic environment was conserved between HR and NHR strains, excluding promoter region variations (eg, PcH2 and P2 promoters within In786) as drivers of differential expression. Pre-exposure of IMP-HR strain HN232 to sub-inhibitory IMP (1, 4, and 32 mg/L) for 24h induced dose-dependent increases in regrowth frequency at 4 and 8 mg/L IMP. Quantitative reverse-transcription PCR (qRT-PCR) and digital PCR (ddPCR) demonstrated that low-dose IMP exposure (1 mg/L, 24h) upregulated blaIMP-45 expression and increased the gene copy number in HN232, whereas the NHR strain HN41 exhibited stringent plasmid regulation.
Conclusion: The study provided critical insights into blaIMP-45-mediated IMP heteroresistance in P. aeruginosa, highlighting plasmid-encoded amplifiable resistance determinants as key modulators of phenotypic adaptability under antibiotic pressure.
Keywords: heteroresistance, carbapenem-resistant Pseudomonas aeruginosa, blaIMP-45, IncP-2 plasmid