Characterization of Tigecycline-Heteroresistant Klebsiella pneumoniae Clinical Isolates From a Chinese Tertiary Care Teaching Hospital
Tigecycline has been used as one of the therapeutic choices for the treatment of infections caused by multidrug-resistant Klebsiella pneumoniae. However, the emergence of tigecycline heteroresistance has led to great challenges in treating these infections. The purpose of this study was to investiga...
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Frontiers Media S.A.
2021-08-01
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| Series: | Frontiers in Microbiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmicb.2021.671153/full |
| _version_ | 1818359210076798976 |
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| author | Qiaoyu Zhang Liping Lin Yuhong Pan Jiansen Chen |
| author_facet | Qiaoyu Zhang Liping Lin Yuhong Pan Jiansen Chen |
| author_sort | Qiaoyu Zhang |
| collection | DOAJ |
| description | Tigecycline has been used as one of the therapeutic choices for the treatment of infections caused by multidrug-resistant Klebsiella pneumoniae. However, the emergence of tigecycline heteroresistance has led to great challenges in treating these infections. The purpose of this study was to investigate whether tigecycline-heteroresistant K. pneumoniae (TGCHR-Kp) exists in clinical isolates, and to further characterize the underlying molecular mechanisms involved in the development of tigecycline-resistant subpopulations. Of the 268 tigecycline-susceptible clinical K. pneumoniae isolates, 69 isolates were selected as tigecycline-heteroresistant candidates in the preliminary heteroresistant phenotypic selection by a modified disk diffusion method, and only 21 strains were confirmed as TGCHR-Kp by the population analysis profile (PAP). Pulsed-field gel electrophoresis (PFGE) analysis demonstrated that all the parental TGCHR-Kp isolates were clonally unrelated, and colonies confirmed as the heteroresistant subpopulation showed no significant differences from their respective parental TGCHR-Kp isolates. Efflux pump inhibitors reversed the tigecycline susceptibility in heteroresistant subpopulations. Mutations in the ramR and soxR genes lead to upregulation of the ramA and soxS transcriptional regulators, which in turn induced overexpression of the AcrAB-TolC efflux pump genes in TGCHR-Kps-resistant subpopulations. Moreover, mutations of rpsJ were also found in resistant subpopulations, which suggested that the rpsJ mutation may also lead to tigecycline resistance. Time-kill assays showed that the efficacy of tigecycline against TGCHR-Kps was weakened, whereas the number of resistant subpopulations was enriched by the presence of tigecycline. Our findings imply that the presence of TGCHR-Kps in clinical strains causes severe challenges for tigecycline therapy in clinical practice. |
| first_indexed | 2024-12-13T20:41:16Z |
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| institution | Directory Open Access Journal |
| issn | 1664-302X |
| language | English |
| last_indexed | 2024-12-13T20:41:16Z |
| publishDate | 2021-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Microbiology |
| spelling | doaj.art-7f5ae55df87d494dbee3b11324d19bd22022-12-21T23:32:08ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2021-08-011210.3389/fmicb.2021.671153671153Characterization of Tigecycline-Heteroresistant Klebsiella pneumoniae Clinical Isolates From a Chinese Tertiary Care Teaching HospitalQiaoyu Zhang0Liping Lin1Yuhong Pan2Jiansen Chen3Department of Nosocomial Infection Control, Fujian Medical University Union Hospital, Fuzhou, ChinaDepartment of Laboratory Medicine, School of Medical Technology and Engineering, Fujian Medical University, Fuzhou, ChinaDepartment of Clinical Laboratory, Fujian Medical University Union Hospital, Fuzhou, ChinaDepartment of Nosocomial Infection Control, Fujian Medical University Union Hospital, Fuzhou, ChinaTigecycline has been used as one of the therapeutic choices for the treatment of infections caused by multidrug-resistant Klebsiella pneumoniae. However, the emergence of tigecycline heteroresistance has led to great challenges in treating these infections. The purpose of this study was to investigate whether tigecycline-heteroresistant K. pneumoniae (TGCHR-Kp) exists in clinical isolates, and to further characterize the underlying molecular mechanisms involved in the development of tigecycline-resistant subpopulations. Of the 268 tigecycline-susceptible clinical K. pneumoniae isolates, 69 isolates were selected as tigecycline-heteroresistant candidates in the preliminary heteroresistant phenotypic selection by a modified disk diffusion method, and only 21 strains were confirmed as TGCHR-Kp by the population analysis profile (PAP). Pulsed-field gel electrophoresis (PFGE) analysis demonstrated that all the parental TGCHR-Kp isolates were clonally unrelated, and colonies confirmed as the heteroresistant subpopulation showed no significant differences from their respective parental TGCHR-Kp isolates. Efflux pump inhibitors reversed the tigecycline susceptibility in heteroresistant subpopulations. Mutations in the ramR and soxR genes lead to upregulation of the ramA and soxS transcriptional regulators, which in turn induced overexpression of the AcrAB-TolC efflux pump genes in TGCHR-Kps-resistant subpopulations. Moreover, mutations of rpsJ were also found in resistant subpopulations, which suggested that the rpsJ mutation may also lead to tigecycline resistance. Time-kill assays showed that the efficacy of tigecycline against TGCHR-Kps was weakened, whereas the number of resistant subpopulations was enriched by the presence of tigecycline. Our findings imply that the presence of TGCHR-Kps in clinical strains causes severe challenges for tigecycline therapy in clinical practice.https://www.frontiersin.org/articles/10.3389/fmicb.2021.671153/fullKlebsiella pneumoniaetigecyclineheteroresistanceefflux pumptime-killing assay |
| spellingShingle | Qiaoyu Zhang Liping Lin Yuhong Pan Jiansen Chen Characterization of Tigecycline-Heteroresistant Klebsiella pneumoniae Clinical Isolates From a Chinese Tertiary Care Teaching Hospital Frontiers in Microbiology Klebsiella pneumoniae tigecycline heteroresistance efflux pump time-killing assay |
| title | Characterization of Tigecycline-Heteroresistant Klebsiella pneumoniae Clinical Isolates From a Chinese Tertiary Care Teaching Hospital |
| title_full | Characterization of Tigecycline-Heteroresistant Klebsiella pneumoniae Clinical Isolates From a Chinese Tertiary Care Teaching Hospital |
| title_fullStr | Characterization of Tigecycline-Heteroresistant Klebsiella pneumoniae Clinical Isolates From a Chinese Tertiary Care Teaching Hospital |
| title_full_unstemmed | Characterization of Tigecycline-Heteroresistant Klebsiella pneumoniae Clinical Isolates From a Chinese Tertiary Care Teaching Hospital |
| title_short | Characterization of Tigecycline-Heteroresistant Klebsiella pneumoniae Clinical Isolates From a Chinese Tertiary Care Teaching Hospital |
| title_sort | characterization of tigecycline heteroresistant klebsiella pneumoniae clinical isolates from a chinese tertiary care teaching hospital |
| topic | Klebsiella pneumoniae tigecycline heteroresistance efflux pump time-killing assay |
| url | https://www.frontiersin.org/articles/10.3389/fmicb.2021.671153/full |
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