High potency of sequential therapy with only β-lactam antibiotics

Elife. 2021 Jul 28;10:e68876. doi: 10.7554/eLife.68876.


Evolutionary adaptation is a major source of antibiotic resistance in bacterial pathogens. Evolution-informed therapy aims to constrain resistance by accounting for bacterial evolvability. Sequential treatments with antibiotics that target different bacterial processes were previously shown to limit adaptation through genetic resistance trade-offs and negative hysteresis. Treatment with homogeneous sets of antibiotics is generally viewed to be disadvantageous as it should rapidly lead to cross-resistance. We here challenged this assumption by determining the evolutionary response of Pseudomonas aeruginosa to experimental sequential treatments involving both heterogenous and homogeneous antibiotic sets. To our surprise, we found that fast switching between only β-lactam antibiotics resulted in increased extinction of bacterial populations. We demonstrate that extinction is favored by low rates of spontaneous resistance emergence and low levels of spontaneous cross-resistance among the antibiotics in sequence. The uncovered principles may help to guide the optimized use of available antibiotics in highly potent, evolution-informed treatment designs.

Keywords: antibiotic resistance; cellular hysteresis; collateral sensitivity; evolutionary biology; evolutionary medicine; pseudomonas aeruginosa; sequential therapy.

Plain Language Summary

Overuse of antibiotic drugs is leading to the appearance of antibiotic-resistant bacteria; this is, bacteria with mutations that allow them to survive treatment with specific antibiotics. This has made some bacterial infections difficult or impossible to treat. Learning more about how bacteria evolve resistance to antibiotics could help scientists find ways to prevent it and develop more effective treatments. Changing antibiotics frequently may be one way to prevent bacteria from evolving resistance. That way if a bacterium acquires mutations that allow it to escape one antibiotic, another antibiotic will kill it, stopping it from dividing and preventing the appearance of descendants with resistance to several antibiotics. In order to use this approach, testing is needed to find the best sequences of antibiotics to apply and the optimal timings of treatment. To find out more, Batra, Roemhild et al. grew bacteria in the laboratory and exposed them to different sequences of antibiotics, switching antibiotics at different time intervals. This showed that sequential treatments with different antibiotics can limit bacterial evolution, especially when antibiotics are switched quickly. Unexpectedly, one of the most effective sequences used very similar antibiotics. This was surprising because using similar antibiotics should lead to the evolution of cross-resistance, which is when a drug causes changes that make the bacterium less sensitive to other treatments. However, in the tested case, cross-resistance did not evolve when antibiotics were switched quickly, thereby ensuring efficiency of treatment. Batra et al. show that alternating sequences of antibiotics may be an effective strategy to prevent drug resistance. Because the experiments were done in a laboratory setting it will be important to verify the results in studies in animals and humans before the approach can be used in medical or veterinary settings. If the results are confirmed, it could reduce the need to develop new antibiotics, which is expensive and time consuming.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / pharmacology*
  • Biological Evolution*
  • Population Dynamics
  • Pseudomonas aeruginosa / drug effects
  • Pseudomonas aeruginosa / physiology*
  • beta-Lactam Resistance*
  • beta-Lactams / pharmacology*


  • Anti-Bacterial Agents
  • beta-Lactams

Grant support

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.