IR@PKUHSC  > 北京大学第二临床医学院
学科主题临床医学
Heteroresistance at the Single-Cell Level: Adapting to Antibiotic Stress through a Population-Based Strategy and Growth-Controlled Interphenotypic Coordination
Wang, Xiaorong1; Kang, Yu2; Luo, Chunxiong3; Zhao, Tong4; Liu, Lin1; Jiang, Xiangdan3; Fu, Rongrong2; An, Shuchang1; Chen, Jichao5; Jiang, Ning1; Ren, Lufeng2; Wang, Qi6; Baillie, J. Kenneth7,8; Gao, Zhancheng1; Yu, Jun2
刊名MBIO
2014
DOI10.1128/mBio.00942-13
5期:1
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Microbiology
资助者Ministry of Science and Technology of the People&prime ; s Republic of China (National High-Tech RD program) ; National 11th &amp ; 12th 5-Years Plan major scientific and technological program ; Ministry of Health of the People&prime ; s Republic of China (Special Fund for Health-Scientific Research in the Public Interest Program) ; Ministry of Science and Technology of the People&prime ; s Republic of China (National High-Tech RD program) ; National 11th &amp ; 12th 5-Years Plan major scientific and technological program ; Ministry of Health of the People&prime ; s Republic of China (Special Fund for Health-Scientific Research in the Public Interest Program)
研究领域[WOS]Microbiology
关键词[WOS]INTERMEDIATE STAPHYLOCOCCUS-AUREUS ; ESCHERICHIA-COLI ; ACINETOBACTER-BAUMANNII ; GENE-EXPRESSION ; MYCOBACTERIUM-TUBERCULOSIS ; FLUCTUATING ENVIRONMENTS ; HETEROGENEOUS RESISTANCE ; KLEBSIELLA-PNEUMONIAE ; SUSCEPTIBILITY ; VANCOMYCIN
英文摘要

Heteroresistance refers to phenotypic heterogeneity of microbial clonal populations under antibiotic stress, and it has been thought to be an allocation of a subset of "resistant" cells for surviving in higher concentrations of antibiotic. The assumption fits the so-called bet-hedging strategy, where a bacterial population "hedges" its "bet" on different phenotypes to be selected by unpredicted environment stresses. To test this hypothesis, we constructed a heteroresistance model by introducing a bla(CTX-M-14) gene (coding for a cephalosporin hydrolase) into a sensitive Escherichia coli strain. We confirmed heteroresistance in this clone and that a subset of the cells expressed more hydrolase and formed more colonies in the presence of ceftriaxone (exhibited stronger "resistance"). However, subsequent single-cell-level investigation by using a microfluidic device showed that a subset of cells with a distinguishable phenotype of slowed growth and intensified hydrolase expression emerged, and they were not positively selected but increased their proportion in the population with ascending antibiotic concentrations. Therefore, heteroresistance-the gradually decreased colony-forming capability in the presence of antibiotic-was a result of a decreased growth rate rather than of selection for resistant cells. Using a mock strain without the resistance gene, we further demonstrated the existence of two nested growth-centric feedback loops that control the expression of the hydrolase and maximize population growth in various antibiotic concentrations. In conclusion, phenotypic heterogeneity is a population-based strategy beneficial for bacterial survival and propagation through task allocation and interphenotypic collaboration, and the growth rate provides a critical control for the expression of stress-related genes and an essential mechanism in responding to environmental stresses.

IMPORTANCE Heteroresistance is essentially phenotypic heterogeneity, where a population-based strategy is thought to be at work, being assumed to be variable cell-to-cell resistance to be selected under antibiotic stress. Exact mechanisms of heteroresistance and its roles in adaptation to antibiotic stress have yet to be fully understood at the molecular and single-cell levels. In our study, we have not been able to detect any apparent subset of "resistant" cells selected by antibiotics; on the contrary, cell populations differentiate into phenotypic subsets with variable growth statuses and hydrolase expression. The growth rate appears to be sensitive to stress intensity and plays a key role in controlling hydrolase expression at both the bulk population and single-cell levels. We have shown here, for the first time, that phenotypic heterogeneity can be beneficial to a growing bacterial population through task allocation and interphenotypic collaboration other than partitioning cells into different categories of selective advantage.

语种英语
所属项目编号2006AA02Z4A9 ; 2012BAI05B02 ; 2009ZX10004-201 ; 2012ZX10004-206 ; 201202011
资助者Ministry of Science and Technology of the People&prime ; s Republic of China (National High-Tech RD program) ; National 11th &amp ; 12th 5-Years Plan major scientific and technological program ; Ministry of Health of the People&prime ; s Republic of China (Special Fund for Health-Scientific Research in the Public Interest Program) ; Ministry of Science and Technology of the People&prime ; s Republic of China (National High-Tech RD program) ; National 11th &amp ; 12th 5-Years Plan major scientific and technological program ; Ministry of Health of the People&prime ; s Republic of China (Special Fund for Health-Scientific Research in the Public Interest Program)
WOS记录号WOS:000332526500050
引用统计
被引频次:5[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/67085
专题北京大学第二临床医学院
作者单位1.Chinese Acad Sci, Inst Microbiol, Beijing, Peoples R China
2.China Aerosp Corp, Cent Hosp, Dept Resp Med, Beijing, Peoples R China
3.Peking Univ, Peoples Hosp, Dept Resp & Crit Care Med, Beijing 100871, Peoples R China
4.Chinese Acad Sci, Beijing Inst Genom, CAS Key Lab Genome Sci & Informat, Beijing, Peoples R China
5.Peking Univ, Ctr Microfluid & Nanotechnol, State Key Lab Artificial Microstruct & Mesoscop P, Beijing 100871, Peoples R China
6.Dalian Med Univ, Hosp 2, Dept Resp Med, Dalian, Liaoning, Peoples R China
7.Univ Edinburgh, Roslin Inst, Div Genet & Genom, Roslin, Midlothian, Scotland
8.Univ Edinburgh, Dept Crit Care Med, Edinburgh, Midlothian, Scotland
推荐引用方式
GB/T 7714
Wang, Xiaorong,Kang, Yu,Luo, Chunxiong,et al. Heteroresistance at the Single-Cell Level: Adapting to Antibiotic Stress through a Population-Based Strategy and Growth-Controlled Interphenotypic Coordination[J]. MBIO,2014,5(1).
APA Wang, Xiaorong.,Kang, Yu.,Luo, Chunxiong.,Zhao, Tong.,Liu, Lin.,...&Yu, Jun.(2014).Heteroresistance at the Single-Cell Level: Adapting to Antibiotic Stress through a Population-Based Strategy and Growth-Controlled Interphenotypic Coordination.MBIO,5(1).
MLA Wang, Xiaorong,et al."Heteroresistance at the Single-Cell Level: Adapting to Antibiotic Stress through a Population-Based Strategy and Growth-Controlled Interphenotypic Coordination".MBIO 5.1(2014).
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