Batra, Aditi; Römhild, RoderichIST Austria ; Rousseau, Emilie; Franzenburg, Sören; Niemann, Stefan; Schulenburg, Hinrich
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.
We would like to thank Leif Tueffers and João Botelho for discussions and suggestions as well as Kira Haas and Julia Bunk for technical support. We acknowledge financial support from the German Science Foundation (grant SCHU 1415/12-2 to HS, and funding under Germany’s Excellence Strategy EXC 2167–390884018 as well as the Research Training Group 2501 TransEvo to HS and SN), the Max Planck Society (IMPRS scholarship to AB; Max-Planck fellowship to HS), and the Leibniz Science Campus Evolutionary Medicine of the Lung (EvoLUNG, to HS and SN). This work was further supported by the German Science Foundation Research Infrastructure NGS_CC (project 407495230) as part of the Next Generation Sequencing Competence Network (project 423957469). NGS analyses were carried out at the Competence Centre for Genomic Analysis Kiel (CCGA Kiel).
Batra A, Römhild R, Rousseau E, Franzenburg S, Niemann S, Schulenburg H. High potency of sequential therapy with only beta-lactam antibiotics. eLife. 2021;10. doi:10.7554/elife.68876
Batra, A., Römhild, R., Rousseau, E., Franzenburg, S., Niemann, S., & Schulenburg, H. (2021). High potency of sequential therapy with only beta-lactam antibiotics. ELife. eLife Sciences Publications. https://doi.org/10.7554/elife.68876
Batra, Aditi, Roderich Römhild, Emilie Rousseau, Sören Franzenburg, Stefan Niemann, and Hinrich Schulenburg. “High Potency of Sequential Therapy with Only Beta-Lactam Antibiotics.” ELife. eLife Sciences Publications, 2021. https://doi.org/10.7554/elife.68876.
A. Batra, R. Römhild, E. Rousseau, S. Franzenburg, S. Niemann, and H. Schulenburg, “High potency of sequential therapy with only beta-lactam antibiotics,” eLife, vol. 10. eLife Sciences Publications, 2021.
Batra A, Römhild R, Rousseau E, Franzenburg S, Niemann S, Schulenburg H. 2021. High potency of sequential therapy with only beta-lactam antibiotics. eLife. 10.
Batra, Aditi, et al. “High Potency of Sequential Therapy with Only Beta-Lactam Antibiotics.” ELife, vol. 10, eLife Sciences Publications, 2021, doi:10.7554/elife.68876.