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  Cellular hysteresis as a principle to maximize the efficacy of antibiotic therapy

Roemhild, R., Gokhale, C. S., Dirksen, P., Blake, C., Rosenstiel, P., Traulsen, A., et al. (2018). Cellular hysteresis as a principle to maximize the efficacy of antibiotic therapy. Proceedings of the National Academy of Sciences of the United States of America, 201810004, pp. 1-6. doi:10.1073/pnas.1810004115.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0002-1BBF-A Version Permalink: http://hdl.handle.net/21.11116/0000-0002-1BC0-7
Genre: Journal Article

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Roemhild, Roderich1, Author              
Gokhale, Chaitanya S.2, Author              
Dirksen, Philipp1, Author              
Blake, Christopher, Author
Rosenstiel, Philip, Author
Traulsen, Arne3, Author              
Andersson, Dan I., Author
Schulenburg, Hinrich1, Author              
Affiliations:
1Max Planck Fellow Group Antibiotic Resistance Evolution, Max Planck Institute for Evolutionary Biology, Max Planck Society, ou_2600692              
2Research Group Theoretical Models of Eco-Evolutionary Dynamics, Department Evolutionary Theory, Max Planck Institute for Evolutionary Biology, Max Planck Society, ou_2355692              
3Department Evolutionary Theory, Max Planck Institute for Evolutionary Biology, Max Planck Society, ou_1445641              

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 Abstract: 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.

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Language(s): eng - English
 Dates: 2018-06-102018-08-162018-09-122018
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1073/pnas.1810004115
BibTex Citekey: Roemhild201810004
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Title: Proceedings of the National Academy of Sciences of the United States of America
  Other : Proceedings of the National Academy of Sciences of the USA
  Other : Proc. Acad. Sci. USA
  Other : Proc. Acad. Sci. U.S.A.
  Abbreviation : PNAS
Source Genre: Journal
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Publ. Info: Washington, D.C. : National Academy of Sciences
Pages: - Volume / Issue: - Sequence Number: 201810004 Start / End Page: 1 - 6 Identifier: ISSN: 0027-8424
CoNE: /journals/resource/954925427230