| 1. |
- Barbosa, Camilo, et al.
(author)
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Evolutionary stability of collateral sensitivity to antibiotics in the model pathogen Pseudomonas aeruginosa
- 2019
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In: eLIFE. - : ELIFE SCIENCES PUBLICATIONS LTD. - 2050-084X. ; 8
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Journal article (peer-reviewed)abstract
- Evolution is at the core of the impending antibiotic crisis. Sustainable therapy must thus account for the adaptive potential of pathogens. One option is to exploit evolutionary trade-offs, like collateral sensitivity, where evolved resistance to one antibiotic causes hypersensitivity to another one. To date, the evolutionary stability and thus clinical utility of this trade-off is unclear. We performed a critical experimental test on this key requirement, using evolution experiments with Pseudomonas aeruginosa, and identified three main outcomes: (i) bacteria commonly failed to counter hypersensitivity and went extinct; (ii) hypersensitivity sometimes converted into multidrug resistance; and (iii) resistance gains frequently caused re-sensitization to the previous drug, thereby maintaining the trade-off. Drug order affected the evolutionary outcome, most likely due to variation in the effect size of collateral sensitivity, epistasis among adaptive mutations, and fitness costs. Our finding of robust genetic trade-offs and drug-order effects can guide design of evolution-informed antibiotic therapy.
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| 2. |
- Roemhild, Roderich, et al.
(author)
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Cellular hysteresis as a principle to maximize the efficacy of antibiotic therapy.
- 2018
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In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 115:39, s. 9767-9772
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Journal article (peer-reviewed)abstract
- 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.
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| 3. |
- Römhild, Roderich, et al.
(author)
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Evolutionary ecology meets the antibiotic crisis : Can we control pathogen adaptation through sequential therapy?
- 2019
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In: EVOLUTION, MEDICINE, AND PUBLIC HEALTH. - : Oxford University Press (OUP). - 2050-6201. ; :1, s. 37-45
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Journal article (other academic/artistic)abstract
- The spread of antibiotic resistance is a global challenge that is fueled by evolution and ecological processes. Therefore, the design of new sustainable therapy should take account of these underlying processes-as proposed within the field of evolutionary medicine, yet usually not receiving the necessary attention from national and international health agencies. We here put the spotlight on a currently neglected treatment strategy: sequential therapy. Changes among antibiotics generate fluctuating selection conditions that are in general difficult to counter by any organism. We argue that sequential treatment designs can be specifically optimized by exploiting evolutionary trade-offs, for example collateral sensitivity and/or inducible physiological constraints, such as negative hysteresis, where pre-exposure to one antibiotic induces temporary hyper-sensitivity to another antibiotic. Our commentary provides an overview of sequential treatment strategies and outlines steps towards their further optimization.
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