Heteroresistance at the single-cell level: adapting to antibiotic stress through a population-based strategy and growth-controlled interphenotypic coordination

Xiaorong Wang, Yu Kang, Chunxiong Luo, Tong Zhao, Lin Liu, Xiangdan Jiang, Rongrong Fu, Shuchang An, Jichao Chen, Ning Jiang, Lufeng Ren, Qi Wang, J Kenneth Baillie, Zhancheng Gao, Jun Yu

Research output: Contribution to journalArticlepeer-review

Abstract

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 blaCTX-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.
Original languageEnglish
Pages (from-to)e00942-13
JournalmBio
Volume5
Issue number1
DOIs
Publication statusPublished - 2014

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