Berit Ada Siedentop


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Siedentop

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Berit Ada

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0000-0003-0802-7681

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2022 - 20245
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Publications 1 - 5 of 5
  • The effect of combining antibiotics on resistance: A systematic review and meta-analysis
    Item type: Journal Article
    Siedentop, Berit Ada; Kachalov, Viacheslav N.; Witzany, Christopher; et al. (2024)
    eLife
    Background: Under which conditions antibiotic combination therapy decelerates rather than accelerates resistance evolution is not well understood. We examined the effect of combining antibiotics on within-patient resistance development across various bacterial pathogens and antibiotics. Methods: We searched CENTRAL, EMBASE, and PubMed for (quasi)-randomised controlled trials (RCTs) published from database inception to 24 November 2022. Trials comparing antibiotic treatments with different numbers of antibiotics were included. Patients were considered to have acquired resistance if, at the follow-up culture, a resistant bacterium (as defined by the study authors) was detected that had not been present in the baseline culture. We combined results using a random effects model and performed meta-regression and stratified analyses. The trials’ risk of bias was assessed with the Cochrane tool. Results: 42 trials were eligible and 29, including 5054 patients, qualified for statistical analysis. In most trials, resistance development was not the primary outcome and studies lacked power. The combined odds ratio for the acquisition of resistance comparing the group with the higher number of antibiotics with the comparison group was 1.23 (95% CI 0.68–2.25), with substantial between-study heterogeneity (I2=77%). We identified tentative evidence for potential beneficial or detrimental effects of antibiotic combination therapy for specific pathogens or medical conditions. Conclusions: The evidence for combining a higher number of antibiotics compared to fewer from RCTs is scarce and overall compatible with both benefit or harm. Trials powered to detect differences in resistance development or well-designed observational studies are required to clarify the impact of combination therapy on resistance. Funding: Support from the Swiss National Science Foundation (grant 310030B_176401 (SB, BS, CW), grant 32FP30-174281 (ME), grant 324730_207957 (RDK)) and from the National Institute of Allergy and Infectious Diseases (NIAID, cooperative agreement AI069924 (ME)) is gratefully acknowledged.
  • Evaluating interventions and defence mechanisms in bacterial symbiosis and pathobionts
    Item type: Doctoral Thesis
    Siedentop, Berit Ada (2024)
  • My host's enemy is my enemy: plasmids carrying CRISPR-Cas as a defence against phages
    Item type: Journal Article
    Siedentop, Berit Ada; Rüegg, Dario; Bonhoeffer, Sebastian; et al. (2024)
    Proceedings of the Royal Society B: Biological Sciences
    Bacteria are infected by mobile genetic elements like plasmids and virulent phages, and those infections significantly impact bacterial ecology and evolution. Recent discoveries reveal that some plasmids carry anti-phage immune systems like CRISPR-Cas, suggesting that plasmids may participate in the coevolutionary arms race between virulent phages and bacteria. Intuitively, this seems reasonable as virulent phages kill the plasmid's obligate host. However, the efficiency of CRISPR-Cas systems carried by plasmids can be expected to be lower than those carried by the chromosome due to continuous segregation loss, creating susceptible cells for phage amplification. To evaluate the anti-phage protection efficiency of CRISPR-Cas on plasmids, we develop a stochastic model describing the dynamics of a virulent phage infection against which a conjugative plasmid defends using CRISPR-Cas. We show that CRISPR-Cas on plasmids provides robust protection, except in limited parameter sets. In these cases, high segregation loss favours phage outbreaks by generating a population of defenceless cells on which the phage can evolve and escape CRISPR-Cas immunity. We show that the phage's ability to exploit segregation loss depends strongly on the evolvability of both CRISPR-Cas and the phage itself.
  • Plasmid co-infection: linking biological mechanisms to ecological and evolutionary dynamics
    Item type: Journal Article
    Igler, Claudia; Huisman, Jana; Siedentop, Berit Ada; et al. (2022)
    Philosophical Transactions of the Royal Society B: Biological Sciences
    As infectious agents of bacteria and vehicles of horizontal gene transfer, plasmids play a key role in bacterial ecology and evolution. Plasmid dynamics are shaped not only by plasmid-host interactions but also by ecological interactions between plasmid variants. These interactions are complex: plasmids can co-infect the same cell and the consequences for the co-resident plasmid can be either beneficial or detrimental. Many of the biological processes that govern plasmid co-infection-from systems that exclude infection by other plasmids to interactions in the regulation of plasmid copy number-are well characterized at a mechanistic level. Modelling plays a central role in translating such mechanistic insights into predictions about plasmid dynamics and the impact of these dynamics on bacterial evolution. Theoretical work in evolutionary epidemiology has shown that formulating models of co-infection is not trivial, as some modelling choices can introduce unintended ecological assumptions. Here, we review how the biological processes that govern co-infection can be represented in a mathematical model, discuss potential modelling pitfalls, and analyse this model to provide general insights into how co-infection impacts ecological and evolutionary outcomes. In particular, we demonstrate how beneficial and detrimental effects of co-infection give rise to frequency-dependent selection on plasmid variants. This article is part of the theme issue 'The secret lives of microbial mobile genetic elements'.
  • Assessing the Role of Bacterial Innate and Adaptive Immunity as Barriers to Conjugative Plasmids
    Item type: Journal Article
    Siedentop, Berit Ada; Mediavilla, Carlota Losa; Kouyos, Roger D.; et al. (2024)
    Molecular Biology and Evolution
    Plasmids are ubiquitous mobile genetic elements, that can be either costly or beneficial for their bacterial host. In response to constant viral threat, bacteria have evolved various immune systems, such as the prevalent restriction modification (innate immunity) and CRISPR-Cas systems (adaptive immunity). At the molecular level, both systems also target plasmids, but the consequences of these interactions for plasmid spread are unclear. Using a modeling approach, we show that restriction modification and CRISPR-Cas are effective as barriers against the spread of costly plasmids, but not against beneficial ones. Consequently, bacteria can profit from the selective advantages that beneficial plasmids confer even in the presence of bacterial immunity. While plasmids that are costly for bacteria may persist in the bacterial population for a certain period, restriction modification and CRISPR-Cas can eventually drive them to extinction. Finally, we demonstrate that the selection pressure imposed by bacterial immunity on costly plasmids can be circumvented through a diversity of escape mechanisms and highlight how plasmid carriage might be common despite bacterial immunity. In summary, the population-level outcome of interactions between plasmids and defense systems in a bacterial population is closely tied to plasmid cost: Beneficial plasmids can persist at high prevalence in bacterial populations despite defense systems, while costly plasmids may face extinction.
Publications 1 - 5 of 5