Bacterial Populations Rapidly Evolve a Time-linked Tolerance to Antibiotics

A team of molecular microbiologists has found that some types of bacteria develop tolerance towards antibiotic treatment by "learning" how to time the length of exposure to the drug and evolving an extended period of dormancy that protects the organisms from the effects of the antibiotic.

Investigators at the Hebrew University of Jerusalem (Israel) followed the evolution of bacterial populations under intermittent exposure to the high concentrations of antibiotics used in the clinic and characterized the evolved strains in terms of both resistance (growth of microorganisms in the constant presence of an antibiotic, provided that the concentration of the antibiotic is not too high) and tolerance (survival of microorganisms during antibiotic treatment, even at high antibiotic concentrations, as long as the duration of the treatment is limited).

Initially bacterial populations were treated with antibiotics for three hours each day. Exposure times were later increased to five and eight hours per day.

By monitoring the phenotypic changes at the population and single-cell levels, the investigators found that after only 10 days the first adaptive change to antibiotic stress became apparent. This was the development of tolerance towards the antibiotic through a major adjustment in the single-cell lag-time distribution, without a change in resistance. They also found that the lag time of bacteria before regrowth was optimized to match the duration of the antibiotic-exposure interval. All bacterial strains adapted by specific genetic mutations, which became fixed in the evolved populations.

The investigators also reported that whole genome sequencing of the evolved strains and restoration of the wild-type alleles allowed the identification of target genes involved in this antibiotic-driven phenotype, which they called "tolerance by lag" (tbl).

The results of this study, which was published in the June 25, 2014, online edition of the journal Nature, demonstrated that bacteria can evolve within days. The investigators expect that better understanding of lag-time evolution as a key determinant of the survival of bacterial populations under high antibiotic concentrations will lead to new approaches to preventing the evolution of antibiotic resistance.

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Hebrew University of Jerusalem