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Rapid evolution is central to the current antibiotic crisis. Sustainable treatments must thus take account of the bacteria’s potential for adaptation. We identified cellular hysteresis as a principle to constrain bacterial evolution. Cellular hysteresis is a persistent change in bacterial physiology, reminiscent of cellular memory, which is induced by one antibiotic and enhances susceptibility toward another antibiotic. Cellular hysteresis increases bacterial extinction in fast sequential treatments and reduces selection of resistance by favoring responses specific to the induced physiological effects. Fast changes between antibiotics are key, because they create the continuously high selection conditions that are difficult to counter by bacteria. Our study highlights how an understanding of evolutionary processes can help to outsmart human pathogens.Antibiotic resistance has become one of the most dramatic threats to global health. While novel treatment options are urgently required, most attempts focus on finding new antibiotic substances. However, their development is costly, and their efficacy is often compromised within short time periods due to the enormous potential of microorganisms for rapid adaptation. Here, we developed a strategy that uses the currently available antibiotics. Our strategy exploits cellular hysteresis, which is the long-lasting, transgenerational change in cellular physiology that is induced by one antibiotic and sensitizes bacteria to another subsequently administered antibiotic. Using evolution experiments, mathematical modeling, genomics, and functional genetic analysis, we demonstrate that sequential treatment protocols with high levels of cellular hysteresis constrain the evolving bacteria by (i) increasing extinction frequencies, (ii) reducing adaptation rates, and (iii) limiting emergence of multidrug resistance. Cellular hysteresis is most effective in fast sequential protocols, in which antibiotics are changed within 12 h or 24 h, in contrast to the less frequent changes in cycling protocols commonly implemented in hospitals. We found that cellular hysteresis imposes specific selective pressure on the bacteria that disfavors resistance mutations. Instead, if bacterial populations survive, hysteresis is countered in two distinct ways, either through a process related to antibiotic tolerance or a mechanism controlled by the previously uncharacterized two-component regulator CpxS. We conclude that cellular hysteresis can be harnessed to optimize antibiotic therapy, to achieve both enhanced bacterial elimination and reduced resistance evolution.
