@article{10812, abstract = {Several promising strategies based on combining or cycling different antibiotics have been proposed to increase efficacy and counteract resistance evolution, but we still lack a deep understanding of the physiological responses and genetic mechanisms that underlie antibiotic interactions and the clinical applicability of these strategies. In antibiotic-exposed bacteria, the combined effects of physiological stress responses and emerging resistance mutations (occurring at different time scales) generate complex and often unpredictable dynamics. In this Review, we present our current understanding of bacterial cell physiology and genetics of responses to antibiotics. We emphasize recently discovered mechanisms of synergistic and antagonistic drug interactions, hysteresis in temporal interactions between antibiotics that arise from microbial physiology and interactions between antibiotics and resistance mutations that can cause collateral sensitivity or cross-resistance. We discuss possible connections between the different phenomena and indicate relevant research directions. A better and more unified understanding of drug and genetic interactions is likely to advance antibiotic therapy.}, author = {Römhild, Roderich and Bollenbach, Mark Tobias and Andersson, Dan I.}, issn = {1740-1534}, journal = {Nature Reviews Microbiology}, keywords = {General Immunology and Microbiology, Microbiology, Infectious Diseases}, pages = {478--490}, publisher = {Springer Nature}, title = {{The physiology and genetics of bacterial responses to antibiotic combinations}}, doi = {10.1038/s41579-022-00700-5}, volume = {20}, year = {2022}, } @article{9046, author = {Römhild, Roderich and Andersson, Dan I.}, issn = {15537374}, journal = {PLoS Pathogens}, number = {1}, publisher = {Public Library of Science}, title = {{Mechanisms and therapeutic potential of collateral sensitivity to antibiotics}}, doi = {10.1371/journal.ppat.1009172}, volume = {17}, year = {2021}, } @article{9746, abstract = {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.}, author = {Batra, Aditi and Römhild, Roderich and Rousseau, Emilie and Franzenburg, Sören and Niemann, Stefan and Schulenburg, Hinrich}, issn = {2050-084X}, journal = {eLife}, publisher = {eLife Sciences Publications}, title = {{High potency of sequential therapy with only beta-lactam antibiotics}}, doi = {10.7554/elife.68876}, volume = {10}, year = {2021}, }