BIOLOGICAL SCIENCES & BIOENGINEERING SEMINAR
Erdal Toprak, Sabancı University
13:40, May 11, 2011
GENOMIC EVOLUTIONARY PATHWAYS TO ANTIBIOTIC RESISTANCE
The evolution of resistance to antibiotics diminishes their therapeutic effectiveness. In clinical and
environmental settings, pathogens can attain high‐level resistance through sequential mutations, yet
adaptation in laboratory studies with fixed drug dosing often consists of a single adaptive step that
removes the selective pressure. Here, we developed a continuous‐culture microbial selection device, the
“morbidostat”, which dynamically adjusts drug concentrations to maintain fixed growth inhibition of
evolving bacterial populations, and investigated evolutionary trajectories towards antibiotic resistance.
We carried out evolution experiments with Escherichia coli in three separate antibiotics, evolving five
populations in parallel per drug. Chloramphenicol and doxycycline resistance increased smoothly by
870‐fold, and 10‐fold respectively, while trimethoprim resistance increased by 1680‐fold in a stepwise
fashion. We identified the genetic changes that elevate resistance by whole‐genome sequencing of the
evolved strains. Mutations on diverse gene sets gradually increased chloramphenicol and doxycycline
resistance, whereas almost all mutations in trimethoprim‐resistant strains appeared on the target
enzyme, dihydrofolate reductase (DHFR). Sequencing the DHFR coding and non‐coding regions from
clones sampled daily within the evolution experiment revealed an ordered sequence for accumulation
of mutations among the parallel evolved populations. These results highlight the importance of specific
mutational trajectories in multi‐step evolution of high‐level antibiotic resistance.
Dr. Toprak received his BS and MS degrees in Physics from Bosphorus University, and his PhD in Biophysics from
University of Illinois at Urbana‐Champaign. During his postdoctoral work he worked at Harvard Medical School. He
joined Sabanci University less than two weeks ago.