Biased partitioning of the multidrug efflux pump AcrAB-TolC underlies long-lived phenotypic heterogeneity

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Science  21 Apr 2017:
Vol. 356, Issue 6335, pp. 311-315
DOI: 10.1126/science.aaf4762

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Drug efflux machinery inherited asymmetrically

In dividing bacterial cells, asymmetric distribution of cell wall constituents occurs between mother cells and their progeny. Asymmetric distribution of efflux machinery in a growing population of bacterial cells results in heterogeneity in antibiotic resistance. One consequence is that in the presence of low levels of antibiotic, older cells tend to live longer than younger cells. Using a microfluidic device to trap and measure dividing cells, Bergmiller et al. showed that AcrAB-TolC, the main multidrug efflux pump of Escherichia coli, clusters at the pole of older cells (see the Perspective by Barrett et al.). As cell division proceeds and daughter cells age, they too gradually accumulate polar efflux pumps.

Science, this issue p. 311; see also p. 247


The molecular mechanisms underlying phenotypic variation in isogenic bacterial populations remain poorly understood. We report that AcrAB-TolC, the main multidrug efflux pump of Escherichia coli, exhibits a strong partitioning bias for old cell poles by a segregation mechanism that is mediated by ternary AcrAB-TolC complex formation. Mother cells inheriting old poles are phenotypically distinct and display increased drug efflux activity relative to daughters. Consequently, we find systematic and long-lived growth differences between mother and daughter cells in the presence of subinhibitory drug concentrations. A simple model for biased partitioning predicts a population structure of long-lived and highly heterogeneous phenotypes. This straightforward mechanism of generating sustained growth rate differences at subinhibitory antibiotic concentrations has implications for understanding the emergence of multidrug resistance in bacteria.

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