Role and mechanism of tigecycline in delaying the resistance of Klebsiella pneumoniae to polymyxin B by inhibiting cpxR
Objective To investigate the effect of polymyxin B (PMB) combined with tigecycline (TGC) on delaying Klebsiella pneumoniae (KP) resistance to PMB, and to analyze the possible mechanisms involved in the induction and delay of resistance. Methods Six clinical isolates of KP strains from the Intens...
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Editorial Office of Journal of Army Medical University
2025-06-01
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| Series: | 陆军军医大学学报 |
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| author | ZHANG Huanhuan ZHANG Huanhuan FENG Wei HUA Shangjun |
| author_facet | ZHANG Huanhuan ZHANG Huanhuan FENG Wei HUA Shangjun |
| author_sort | ZHANG Huanhuan |
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| description | Objective To investigate the effect of polymyxin B (PMB) combined with tigecycline (TGC) on delaying Klebsiella pneumoniae (KP) resistance to PMB, and to analyze the possible mechanisms involved in the induction and delay of resistance. Methods Six clinical isolates of KP strains from the Intensive Care Unit of First Affiliated Hospital of Army Medical University were subjected and then induced with PMB at 1/2 minimal inhibitory concentration (MIC) alone or combined with TGC at 1/2 and 1/4 MIC, respectively. The MIC changes of PMB in these strains were monitored over 14 consecutive passages. The strain 686K, which showed the most significant delay in resistance, was selected for further analysis. Differences in gene and protein expression were examined among the wild-type strain 686K, PMB-induced resistant strain (686K·R), and PMB combined with TGC delayed resistant strain (686K·DR) using transcriptome sequencing, qRT-PCR, and proteomics. Relevant target genes during the delay of resistance were analyzed through literature and bioinformatics analyses. Additionally, cpxR gene knockout strain 686K/ΔcpxR∷Apr and its complementation strain 686K/ΔcpxR∷Apr/pRK415-cpxR were constructed using homologous recombination technology to assess the expression levels of resistance-related genes and changes in MIC after induction in vitro. Results Under sub-MIC(1/2) PMB alone, resistance developed in all 6 KP strains within 2 d, while, the combination with TGC significantly delayed the development of resistance. Transcriptomic and proteomic analyses indicated that in strain 686K·R, the expression levels of the PhoP/Q two-component system, lipopolysaccharide (LPS) modification enzymes, and efflux pump systems were significantly up-regulated (|Log2FC|≥2, P<0.0001), while TGC co-administration markedly inhibited these expression changes. The cpxR deletion and complementation strains were successfully constructed. The expression levels of resistance-related genes phoP, pmrD, and acrA were decreased in the cpxR deletion strain (P<0.001), and the resistance was delayed until day 6 under PMB monotherapy, whereas the complementation strain restored the resistance phenotype by day 2. In the absence of cpxR, the effect of PMB when combined with TGC on delaying resistance did not differ from that observed with PMB monotherapy. Conclusion The combination of PMB and TGC can delay KP resistance to PMB. cpxR, as a critical regulatory factor, can impact PMB resistance by modulating LPS modifications and the expression of the AcrAB-TolC efflux pump, and plays an important regulatory role in the process of resistance induction.
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| format | Article |
| id | doaj-art-2abd9b7bc73e4f42b501c374b5fc47b9 |
| institution | Kabale University |
| issn | 2097-0927 |
| language | zho |
| publishDate | 2025-06-01 |
| publisher | Editorial Office of Journal of Army Medical University |
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| series | 陆军军医大学学报 |
| spelling | doaj-art-2abd9b7bc73e4f42b501c374b5fc47b92025-08-20T03:27:52ZzhoEditorial Office of Journal of Army Medical University陆军军医大学学报2097-09272025-06-0147121401141210.16016/j.2097-0927.202504025Role and mechanism of tigecycline in delaying the resistance of Klebsiella pneumoniae to polymyxin B by inhibiting cpxRZHANG Huanhuan0ZHANG Huanhuan1FENG Wei2HUA Shangjun 3Department of Pharmacy， the Second Affiliated Hospital of Chongqing Medical University， ChongqingDepartment of Pharmacy， First Affiliated Hospital， Army Medical University （Third Military Medical University）， Chongqing， ChinaDepartment of Pharmacy， First Affiliated Hospital， Army Medical University （Third Military Medical University）， Chongqing， ChinaDepartment of Pharmacy， the Second Affiliated Hospital of Chongqing Medical University， ChongqingObjective To investigate the effect of polymyxin B (PMB) combined with tigecycline (TGC) on delaying Klebsiella pneumoniae (KP) resistance to PMB, and to analyze the possible mechanisms involved in the induction and delay of resistance. Methods Six clinical isolates of KP strains from the Intensive Care Unit of First Affiliated Hospital of Army Medical University were subjected and then induced with PMB at 1/2 minimal inhibitory concentration (MIC) alone or combined with TGC at 1/2 and 1/4 MIC, respectively. The MIC changes of PMB in these strains were monitored over 14 consecutive passages. The strain 686K, which showed the most significant delay in resistance, was selected for further analysis. Differences in gene and protein expression were examined among the wild-type strain 686K, PMB-induced resistant strain (686K·R), and PMB combined with TGC delayed resistant strain (686K·DR) using transcriptome sequencing, qRT-PCR, and proteomics. Relevant target genes during the delay of resistance were analyzed through literature and bioinformatics analyses. Additionally, cpxR gene knockout strain 686K/ΔcpxR∷Apr and its complementation strain 686K/ΔcpxR∷Apr/pRK415-cpxR were constructed using homologous recombination technology to assess the expression levels of resistance-related genes and changes in MIC after induction in vitro. Results Under sub-MIC(1/2) PMB alone, resistance developed in all 6 KP strains within 2 d, while, the combination with TGC significantly delayed the development of resistance. Transcriptomic and proteomic analyses indicated that in strain 686K·R, the expression levels of the PhoP/Q two-component system, lipopolysaccharide (LPS) modification enzymes, and efflux pump systems were significantly up-regulated (|Log2FC|≥2, P<0.0001), while TGC co-administration markedly inhibited these expression changes. The cpxR deletion and complementation strains were successfully constructed. The expression levels of resistance-related genes phoP, pmrD, and acrA were decreased in the cpxR deletion strain (P<0.001), and the resistance was delayed until day 6 under PMB monotherapy, whereas the complementation strain restored the resistance phenotype by day 2. In the absence of cpxR, the effect of PMB when combined with TGC on delaying resistance did not differ from that observed with PMB monotherapy. Conclusion The combination of PMB and TGC can delay KP resistance to PMB. cpxR, as a critical regulatory factor, can impact PMB resistance by modulating LPS modifications and the expression of the AcrAB-TolC efflux pump, and plays an important regulatory role in the process of resistance induction. https://aammt.tmmu.edu.cn/html/202504025.htmlklebsiella pneumoniaepolymyxin btigecyclinecombination therapycpxr |
| spellingShingle | ZHANG Huanhuan ZHANG Huanhuan FENG Wei HUA Shangjun Role and mechanism of tigecycline in delaying the resistance of Klebsiella pneumoniae to polymyxin B by inhibiting cpxR 陆军军医大学学报 klebsiella pneumoniae polymyxin b tigecycline combination therapy cpxr |
| title | Role and mechanism of tigecycline in delaying the resistance of Klebsiella pneumoniae to polymyxin B by inhibiting cpxR |
| title_full | Role and mechanism of tigecycline in delaying the resistance of Klebsiella pneumoniae to polymyxin B by inhibiting cpxR |
| title_fullStr | Role and mechanism of tigecycline in delaying the resistance of Klebsiella pneumoniae to polymyxin B by inhibiting cpxR |
| title_full_unstemmed | Role and mechanism of tigecycline in delaying the resistance of Klebsiella pneumoniae to polymyxin B by inhibiting cpxR |
| title_short | Role and mechanism of tigecycline in delaying the resistance of Klebsiella pneumoniae to polymyxin B by inhibiting cpxR |
| title_sort | role and mechanism of tigecycline in delaying the resistance of klebsiella pneumoniae to polymyxin b by inhibiting cpxr |
| topic | klebsiella pneumoniae polymyxin b tigecycline combination therapy cpxr |
| url | https://aammt.tmmu.edu.cn/html/202504025.html |
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