Bacteria’s drug resistance is not affected by genetic tradeoffs

According to a study published recently in the eLife journal, bacteria can still acquire antibiotic resistance even in the face of complex genetic compromises, or tradeoffs, related to different concentrations of antibiotics.

Image Credit: Kateryna Kon/Shutterstock.com

A growing health crisis across the world is the rapid evolution of bacteria that are impervious to antibacterial drugs. The discoveries offer a useful and deeper understanding of how various drug concentrations impact the emergence of resistance in Escherichia coli (E. coli) bacteria, which can lead to fatal blood infections.

Such antibiotic resistance can arise when a genetic mutation takes place in a single bacterium that enables it to tolerate the drug. The new resistant strain increases in number, while the vulnerable pathogens die. The bacteria become highly resistant to antibiotics only when multiple mutations take place, and each mutation potentially comes with certain tradeoffs.

For instance, a mutation that enables the bacteria to tolerate an antibiotic drug may slow down the growth of the organism in the absence of an antibiotic. If there are more tradeoffs on the evolutionary path to drug resistance, it would make it harder for the resistance to emerge.

If the fitness landscape is smooth with few tradeoffs, the evolving bacterial population can easily become resistant, whereas in a rugged landscape with lots of tradeoffs one expects it to get stuck at suboptimal peaks and to be less likely to become resistant.”

Suman Das, Study Lead Author and Research Associate, Institute for Biological Physics, University of Cologne

Das collaborated with Susana Direito, Bartlomiej Waclaw, and Rosalind Allen from the University of Edinburgh, United Kingdom, to learn more about the effect of different concentrations of antibiotics on the evolution of resistance in E. coli.

The researchers exposed the pathogens to different concentrations of the ciprofloxacin antibiotic. They then monitored the bacteria’s growth rate in these conditions and the tradeoffs that took place. Based on the researchers’ data, Das developed a mathematical model.

This mathematical model demonstrated that the paths to resistance become harder to traverse when there are tradeoffs. However, in contrast to the researchers’ expectation, the barriers produced by the tradeoffs did not make the evolution of resistance less likely.

The evolution of resistance wasn’t constrained by fitness landscape ruggedness. At the same time, as more tradeoffs emerged, it became more difficult for us to predict the evolutionary path the bacteria would take towards resistance.”

Suman Das, Study Lead Author and Research Associate, Institute for Biological Physics, University of Cologne

But the researchers’ model did suggest that the pathogens may reverse the path and regain antibiotic susceptibility when faced with lower drug concentrations.

Our model provides a principled framework for addressing the evolution of antibiotic resistance in clinical and environmental settings, where drug concentrations vary widely. It could one day be used to help scientists design new drugs or treatment protocols that prevent or slow the emergence of antibiotic resistance.”

Joachim Krug, Study Senior Author and Group Leader, Institute for Biological Physics, University of Cologne