Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - Tolerome (Evolution of antibiotic tolerance in the \'wild\': A quantitative approach)

Teaser

The failure of antibiotic treatments is a major concern worldwide. Resistance is a major determinant in the survival for bacteria under antibiotics. However, it is often observed that bacteria become recalcitrant to antibiotics treatments, without developing resistance, a...

Summary

The failure of antibiotic treatments is a major concern worldwide. Resistance is a major determinant in the survival for bacteria under antibiotics. However, it is often observed that bacteria become recalcitrant to antibiotics treatments, without developing resistance, a phenomenon termed “tolerance”. The extent and importance of tolerance for infections is still unknown and the subject of intense debate. It has been proposed in a number of mathematical models that tolerance and persistence (a form of tolerance that affects only a sub-population of bacteria) may promote the evolution of resistance. The overall objectives of this framework is to determine the importance of tolerance for the subsequent evolution of antibiotic resistance and to develop experimental and mathematical tools for the identification and analysis of tolerance. By following how resistance develops first in vitro and then in patients, we should be able to identify the factors necessary for the evolution of resistance and eventually, be able to find ways to slow down the evolution of resistance.

Work performed

We have now shown, by performing experimental evolution experiments under the high concentrations of antibiotics typically achieved in patients, that resistance evolves always first through a tolerance step. In other words, in all our experiments in which resistance to antibiotics evolved, the first mutations that fixed in the population were in fact tolerance mutations, and resistance mutations appeared only as a second step on top of the tolerant background. We were able to reconstruct the evolutionary trajectories in several strains and analyze quantitatively the separate contributions of tolerance and resistance mutations to fitness. Our mathematical analysis identifies tolerance as a key factor to promote the subsequent emergence of resistance. Therefore, preventing tolerance may impede the evolution of resistance.
In addition, we have now developed tools to detect tolerance directly on clinical isolates of bacteria in hospitals.

Final results

Now that we have understood the evolutionary path to resistance in vitro, we will use this new understanding, as well as the new tools adapted for the clinical setting, in order to follow the evolution of tolerance in patients.
Our goal will be to identify the similarities and differences between the in host evolution and the in vitro results. We expect to be able to translate our quantitative and mathematical understanding into new avenues for preventing the evolution of antibiotic resistance in the clinical setting.