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Heterogeneity in efflux pump expression predisposes antibiotic-resistant cells to mutation

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Science  09 Nov 2018:
Vol. 362, Issue 6415, pp. 686-690
DOI: 10.1126/science.aar7981

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Efflux pumps and mutation

Antibiotic resistance is an alarming and growing challenge. Bacteria show great heterogeneity in growth and mutation rates. Such variability allows some cells to persist during transient antibiotic exposure. During this persistent phase, mutations accumulate, which can result in selection for full-blown antibiotic resistance. El Meouche and Dunlop found that increased expression of efflux pumps on some cells affords them some relief from antibiotic toxicity. But up-regulating efflux pumps is costly for the bacteria, reducing growth rate and expression of MutS, a protein involved in DNA mismatch repair. These changes thus lift the lid on increased levels of bacterial mutation.

Science, this issue p. 686

Abstract

Antibiotic resistance is often the result of mutations that block drug activity; however, bacteria also evade antibiotics by transiently expressing genes such as multidrug efflux pumps. A crucial question is whether transient resistance can promote permanent genetic changes. Previous studies have established that antibiotic treatment can select tolerant cells that then mutate to achieve permanent resistance. Whether these mutations result from antibiotic stress or preexist within the population is unclear. To address this question, we focused on the multidrug pump AcrAB-TolC. Using time-lapse microscopy, we found that cells with higher acrAB expression have lower expression of the DNA mismatch repair gene mutS, lower growth rates, and higher mutation frequencies. Thus, transient antibiotic resistance from elevated acrAB expression can promote spontaneous mutations within single cells.

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