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

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 expression have lower expression of the DNA mismatch repair gene , lower growth rates, and higher mutation frequencies. Thus, transient antibiotic resistance from elevated expression can promote spontaneous mutations within single cells.